Projects

Under the guidance of our Scientific Advisory Board through a carefully managed grants process, FPWR selects research projects based on the collaborative input of researchers and parents, choosing projects that are both scientifically meritorious and highly relevant for individuals with PWS and their families.

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The Effect of Growth Hormone Treatment on Premature Aging and Quality of Life in Adults with PWS

Funded Year: 2024

In PWS individuals aged 40 and up, quality of life (QoL) seems to be mainly impaired by premature aging, and premature aging in PWS seems to be less prominent in adults treated with growth hormone (GH). This project will investigate whether GH indeed slows down premature aging in PWS, by using a large group of older adults in the Netherlands that...

The role of lateral septum neurons in the pathogenesis of Prader - Willi Syndrome

Funded Year: 2024

Dr. Azevedo is interested in a particular set of neurons (the lateral septum, LS, neurons) in the brain that express the PWS-region gene, MAGEL2, since these neurons may be important in controlling feeding behavior. Here, she will investigate whether LS neurons behave differently in PWS mice compared to ‘wild-type mice’, potentially identifying a...

Molecular Underpinnings of Prader-Willi Syndrome

Funded Year: 2024

Dr. Carmichael has been investigating the changes in gene expression of PWS cells lacking SNORD116 genes compared to typical cells and has identified a set of 40 genes that are differentially expressed. In year 2 they will further characterize these genes and their role in PWS and will examine how SNORD116 controls their expression.

Non-coding RNAs in neuronal differentiation and PWS (Year 2)

Funded Year: 2024

Dr. Tollervey is an expert in snoRNA biology. He has been investigating the snoRNAs in the PWS region and has found that loss of the SNORD116 genes alters neuronal maturation in PWS cells (https://www.biorxiv.org/content/10.1101/2023.10.24.563766v1). In year 2 of his funded project, they will use specialized techniques to identify the RNAs and...

Spatial Molecular Imaging of the Human PWS Hypothalamus

Funded Year: 2024

Dr. Yosten is using a combined spatial imaging approach to perform a detailed analysis of the proteins and genes found in hypothalamus of individuals with PWS, in comparison to typical individuals. They will build a data-sharing platform that can be used by the entire scientific community to analyze gene and protein differences in PWS brain...

Prefrontal cortex glutamatergic neurons as a target for metabolic and cognitive symptoms in a mouse model of PWS (Year 2)

Funded Year: 2024

Dr. Ross has been investigating a particular region of the brain (medial prefrontal cortex) and class of neurons in PWS mice, to understand their link to cognitive and metabolic changes in PWS. They will determine whether stimulating these neural circuits in the brains of PWS mice reduces food intake and improves learning, potentially identifying...

Obsessive-compulsive and psychotic-like behaviors across PWS subtypes: Developmental considerations

Funded Year: 2024

Dr. Evans has previously developed a well-validated measure of rigidity and obsessive-compulsive behaviors, as well as behaviors associated with psychosis. Here, he will work with the Global PWS Registry team to recruit families to complete these assessments three times over a year and see if they are well-suited for the PWS population. These...

Defining isoform diversity conserved in the brain and blood, related to the severity of Prader-Willi syndrome

Funded Year: 2024

Dr. Godler has been investigating cell-specific changes in gene expression in blood and brain tissue samples from individuals with PWS, with the goal of developing blood-based biomarkers of PWS severity. Here his collaborative will apply newer technologies to look at genes and proteins that are differentially expressed in PWS and use that...

In vivo implementation of hypothalamus-specific exosomes to reverse the impact of Snord116 deletion

Funded Year: 2024

Dr. Lee and colleagues have been investigating the use of exosomes (small vesicles released from cells) to carry PWS genes to the hypothalamus in PWS mouse models, as a first step to gene therapy for PWS. Here they will use their engineered exosomes to test whether delivery of the PWS genes can reverse the PWS features seen in the mice.

Analysis of Delayed Neural Development in PWS DPSC Neurons (Year 2)

Funded Year: 2024

Dr. Reiter has used stem cells derived from baby teeth to look at differences in how PWS neurons in a dish develop compared to typical neurons. He has found changes in circadian rhythm and timing of development. Year 2 work will focus on ‘rescuing’ these characteristics by delivering different PWS-region genes to the cells.

Using designer milk exosomes for restoring MAGEL2 expression in the brains of Magel2 knockout mice

Funded Year: 2024

Exosomes are nonviral fragments of cells that can be used for the delivery of genes. Dr. Zempleni has developed targeted milk exosomes and will apply that approach to deliver a critical gene from the PWS region, Magel2, to a mouse model of PWS.

An innovative non-viral delivery of CRISPR/dCas9 epigenome editing-based therapy for Prader-Willi Syndrome

Funded Year: 2024

Dr. Lu will use an innovative delivery system to achieve CRISPR gene activation in a new mouse model of PWS.

Epigenome Editing for Stable Reactivation of Maternal PWS Genes

Funded Year: 2024

Dr. Gersbach continues his work examining advanced CRISPR tools to understand the regulation of gene activity in the PWS region and optimize gene activation strategies.

Revealing the Molecular Architecture of PWS Through Large Language Models for Targeted Drug Repurposing

Funded Year: 2024

Dr. Singh will apply artificial intelligence to PWS datasets to glean new information about pathways disrupted in PWS and possible targets for therapy.

Cellular and molecular basis for obesity in PWS (Year 2)

Funded Year: 2024

This renewal application builds on excellent work to date from the Friedman lab, which has identified a new subset of neurons in the hypothalamus and a novel gene that may be driving hyperphagia in PWS. They will explore how Magel2 impacts the function in these neurons and whether a pharmacological approach can impact their newly identified...

Genetic Determinants Of Behavioral Physical And Physiological Characteristics of PWS (Year 2)

Funded Year: 2024

This second year of funding expands Dr. Bochukova's work to understand how genetic variants outside the PWS region influence the frequency and severity of symptoms associated with PWS.

Endoplasmic reticulum (ER) chaperones in Prader-Willi syndrome: Therapy and mechanisms

Funded Year: 2024

Dr. Nicholls has identified deficits in a set of proteins that facilitate the folding and maturation of other proteins, ER chaperone proteins. He believes deficits of these proteins in the pancreas is an important contributor to endocrine dysfunction in PWS. Here he will assess the ability of drugs that activate these chaperone proteins to rescue...

Similar metabolic pathways are affected in both Prader-Willi Syndrome and Congenital Myasthenic Syndrome-22

Funded Year: 2024

Dr. Creemers has found that PWS has molecular similarities to another genetic disorder called CMS22. Individuals with CMS22 deficiency also have hypotonia and poor growth, followed by the development of hyperphagia. Here the lab will evaluate if the protein associated with CMS22 (PREPL) can rescue the PWS neonatal characteristics, using a mouse...

Novel functions and translation mechanisms involving SNURF and neural-specific SmN spliceosomal protein

Funded Year: 2024

One of the major genes in the PWS critical region, SNURF-SNRPN, is relatively understudied. Here, Dr. McManus will use cell models of human brain, pancreas and heart to understand the function of the proteins that this gene produces.

Elucidating Phenotypic Differences between PWS and SYS: Exploring MAGEL2 Fate in Human Neurons

Funded Year: 2024

Dr. Laugsch's group will examine the normal function of the MAGEL2 protein compared to MAGEL2 harboring SYS mutations, analyzing neuronal growth and function in the laboratory dish.

Evaluating direct play intervention for preschoolers and long-term follow-up of the PRETEND program

Funded Year: 2024

The PRETEND program, developed by Dr. Dimitropoulos and her team, has been shown to improve aspects of social, emotional, and cognitive functioning in preschool and school age children with PWS. The purpose of this funded project is to make the PRETEND Program available to more families by establishing a platform to train interventionists to use...

Emergency Department and Inpatient Care of Individuals with PWS

Funded Year: 2024

Understanding the greatest clinical challenges is important in PWS, but there are individuals with PWS who are not participating in registry studies or surveys. Insurance claims data can be used to identify most people with PWS receiving care in the US. This project will analyze a vast database of claims from emergency departments and hospitals...

Transcriptome-wide identification and functional annotation of PWS-encoded SNORD targets

Funded Year: 2024

The SNORD genes are known to be very important in PWS, but there is a lack of appropriate tools to study the target and function of these genes. Dr. He and his team have developed two new methods that can map the targets of the SNORD genes. They will apply these new methods to mouse models and human cell lines with a deficiency in PWS-encoded...

The role of oxytocin receptor-expressing astrocytes in Prader- Willi and Schaaf-Yang syndromes (Year 2)

Funded Year: 2024

Dr. Schaaf’s previous research showed that the ‘support cells’ in the brain (astrocytes) express receptors for oxytocin, are critically involved in the modulation of social behavior and anxiety, and that there are differences in both number and anatomical location of these astrocytes in healthy mice compared to a PWS mouse model. In this second...

Investigating the role of Snord116 in ribosome biology

Funded Year: 2024

Through previous work using a new optimized method, Dr. Whipple discovered that Snord116, a driver of PWS, directly interacts with ribosomes, the machinery that produces proteins in the cell in mouse neurons. In this funded project, they will apply their optimized method to human neurons to ask if the interaction between SNORD116 and ribosomes is...

Postdoctoral Fellowship to Investigate the Molecular Biology of MAGEL2 in Schaaf-Yang and Prader-Willi Syndromes

Funded Year: 2023

Studies using cell and animal models are needed to better understand the normal function of MAGEL2 and how mutations or loss of the protein underlies both the PWS and SYS phenotypes. This funded project will support a postdoctoral fellow in Dr. Christian Schaaf’s lab to investigate the molecular biology of MAGEL2 in both PWS and SYS. This will...

Wearable Device Use for Heart Rate Variability Measurement for Objective Assessment of Hyperphagia

Funded Year: 2023

Directly measured, objective outcomes are needed for Prader-Willi Syndrome (PWS) clinical trials for accurate assessment of treatment efficacy. We will conduct in person focus groups of primary caregivers of children between 8-17 years with PWS to review potential options for wearable devices and options for daily diaries/data entry, and use this...

Using Functional Near-Infrared Spectroscopy to Identify Biomarkers of Skin Picking Behavior in PWS

Funded Year: 2023

In previous research, Dr. Hall has found that altered internal bodily cues (interoceptive processes), such as pain, itch, and sensual touch, may be involved in skin picking behavior in PWS. Here, he will employ a sophisticated brain imaging method called functional near-infrared spectroscopy (fNIRS), which allows brain activity to be measured...

Application of Advanced Neuroimaging Techniques in Prader-Willi Syndrome

Funded Year: 2023

This research will use state of the art neuroimaging techniques to advance our understanding of the neurobiology of two of the most challenging and difficult to manage aspects of PWS: hyperphagia and psychosis. The investigators will determine if imaging can detect changes in hypothalamic function in relation to eating behavior in PWS as well as...

Mapping the hypothalamic functional architecture underlying appetite control in the PWS brain

Funded Year: 2023

Working with the Autism BrainNet, Dr. Yeo and his team will examine hypothalamic tissue samples from six individuals with PWS. The research team apply cutting edge molecular analysis to these precious samples and to map the architecture of the PWS hypothalamus, providing insight into the changes underlying appetite control. They will create a...

Integration of Serum Metabolome and Gut Microbiome to Identify Host-Microbe Metabolic Interactions in PWS

Funded Year: 2023

This project will explore how the gut microbiome influences metabolic health in PWS. Dr. Haqq is collaborating with one of the world’s leading metabolomics lab (Dr. David Wishart) to characterize ‘metabolite’ profiles in children and adolescents with PWS and explore the links between blood metabolites, the gut microbe, and metabolic health in...

Role of Microbial Metabolites in Regulating Hypothalamic Pathways Involved in Feeding Behavior

Funded Year: 2023

The probiotic supplement, BPL1, shows promise improving metabolism and behavior in people with PWS, but more work is needed to understand how this gut microbiome intervention can be optimized. This project aims to understand how probiotic supplementation improves metabolic and mental health in individuals with PWS by influencing brain circuits...

Deciphering the role of olfaction in Prader-Willi Syndrome

Funded Year: 2023

These researchers hypothesize that PWS is associated with changes in the perception of food odors, which may drive some aspects of hyperphagia. In this study, Drs. Steculorum and Tauber will examine the role of olfaction in both patients with PWS and a mouse model of PWS, and will explore how one potential treatment, oxytocin, impacts the...

MCH neuron dysregulation in the pathophysiology of Prader-Willi Syndrome

Funded Year: 2023

People with PWS have abnormally high amounts of REM sleep and inappropriate occurrence of REM sleep in the middle of active wake periods. A specific population of neurons in the lateral hypothalamus secretes a neuroactive substance called melanin-concentrating hormone (MCH), which control REM sleep. To determine if MCH neurons are overactive in...

Advance Development of a Cell-Based Test for Screening of Drugs to Correct Circadian Rhythm Defects in PWS

Funded Year: 2023

The purpose of this project is to develop a cellular assay specific to circadian rhythm defects identified by the Reiter laboratory. The eventual goal is to use this assay to screen for compounds that can normalize these circadian defects, potentially identifying drugs that would address developmental and metabolic changes that accompany...

The Prader-Willi PreClinical Animal Network (PCAN):Establishing a computational platform for the PCAN initiative

Funded Year: 2023

FPWR has established the Pre-clinical Animal Network (FPWR-PCAN) initiative to rigorously define the characteristics (phenotype) of PWS mouse models compared to ‘wild type’ or typical mice. This project will transform this effort into a valuable translational platform for the PWS scientific community by conducting multi-step, comprehensive...

Targeting SMCHD1 to address the underlying cause of PWS

Funded Year: 2023

Inhibiting SMCHD1 is a potential new treatment for PWS and SYS. In the first year of this study Dr. Blewitt provided evidence that SMCHD1 acts in a similar way in human cells and quantitated the level of gene activation that occurs in a mouse model when SMCHD1 is removed. In this second year of funding, Dr. Blewitt will attempt to determine what...

Evaluation of CART as a potential therapeutic target for PWS using a rat model

Funded Year: 2023

The goal of this study is to further evaluate whether the hormone, CART, is a viable therapeutic target for the treatment of the insatiable appetite associated with Prader Willi Syndrome (PWS). In this application, we propose to continue our studies through the following Aims: 1. determine if injection of CART can decrease appetite in obese...

The Role of Microglia in Prader-Willi Syndrome and a Hypothalamic Gene Therapy

Funded Year: 2023

Recently, Dr. Cao validated the safety and efficacy of a novel brain-directed gene therapy (BDNF) for metabolic and behavioral deficits observed in a preclinical mouse model of PWS, and identified BDNF as a potential therapeutic target to treat metabolic and behavioral aspects of PWS. Follow-up studies by our group investigated the genetic...

Determining beloranib’s mechanism of action to inform novel drug targets for Prader-Willi syndrome

Funded Year: 2023

Dr. Mitchell and her team have been investigating how beloranib, a drug that effectively reduced hyperphagia and induced weight loss in individuals with PWS, worked. By defining downstream effectors of beloranib’s hyperphagia-reducing action, they hope to identify a safe and effective drug to treat hyperphagia in PWS. Dr. Theresa Strong, Director...

Preparatory studies to enable generation of a genetically engineered marmoset as a model system for Prader-Willi syndrome

Funded Year: 2023

Drs. Urban and Parker will examine genomic data from marmosets to lay the groundwork for the potential development of a novel animal model of PWS. The feasibility of generating a genetically engineered marmoset model for PWS will be evaluated and a detailed plan for generating this model will be generated.

Delineating the role of MAGEL2 in impaired neurohormonal balance in PWS and SYS: Is there a way to overcome MAGEL2 requirement in hypothalamus?

Funded Year: 2023

Dr. Fon Tacer’s studies will provide mechanistic insights into how loss of the PWS-region gene, MAGEL2, results in deficits of secretory granules (SG), which are essential for the proper release of hormones from cells. Such an understanding is critical for determining how to restore neuroendocrine function for therapeutic purposes. This project...

Noninvasive Neuromodulation of a Novel Cerebellar Satiety Circuit in PWS

Funded Year: 2023

Our recent research identified a new brain pathway, the cerebellum-ventral striatum circuit, in regulating appetite and satiation. In the proposed study, we plan to test whether safe, non-invasive modulation of this circuit, using a technique called transcranial magnetic stimulation (TMS), can impact the function of this circuit and reduce food...

shRNA/AAV9 Gene Therapy for the Treatment of Prader-Willi Syndrome

Funded Year: 2022

This research team is exploring a novel approach to activate maternal gene expression from the PWS region of chromosome 15, using a small piece of RNA (short hairpin RNA) to interfere with a protein that silences the maternal chromosome.

Investigation of cerebellar control of striatal dopamine activity and food intake in PWS

Funded Year: 2022

These researchers have demonstrated that activation of a distinct class of cerebellar neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. In this proposal, we will characterize this novel cerebellar satiation network and evaluate whether this network is disrupted in PWS mouse models and...

PWS Smart-Start – A Randomized Clinical Trial

Funded Year: 2022

This project aims to evaluate a parent training program (PWS Smart Start) for helping caregivers develop the skills they need to address challenging behavior and skill deficits common among children with Prader-Willi Syndrome. This project begins to lay the foundation for behavior analytic services for children with PWS, with the end goal of...

In their own voices: Developing a self-report measure of Hyperphagia for Individuals with PWS

Funded Year: 2022

Currently, hyperphagia is often assessed by proxy informants on the Hyperphagia Questionnaires. Leveraging insights from previous research -- and with input from a PWS Advisory Board, PWS focus groups and our own experience in developing other PWS-specific measures—this project will develop a self-report measure of hyperphagic symptoms for...

Engineering epigenome editing tools for sustained reactivation of maternal PWS genes (Year 2)

Funded Year: 2022

This proposal investigates the development of a potential epigenetic therapy for PWS. Year 1 of this project showed the researchers were able to reactivate several maternal silenced PWS genes. In year 2, they will determine the epigenetic requirements for a uniform and stable reactivation of the maternal PWS region in human cells using transient...

Defining Cell-Type Specific Signatures and Dysregulated Pathways from Blood and Brain in PWS (Year 2)

Funded Year: 2022

In year 1 of this project we found increased UBE3A levels in white blood cells was linked to more severe autism features, but only in non-deletion PWS (most matUPD). In year 2, we will analyze the dataset created in year 1 to help us understand how activity of UBE3A and other key genes (related to inflammatory and other dysregulated pathways)...

Assessing DGKK Signaling Pathway as a SNORD116 Target in the Pathogenesis of PWS

Funded Year: 2022

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

Targeting the orexin system to treat Prader-Willi syndrome associated hyperphagia

Funded Year: 2022

One effect of the lack of Magel2 in PWS is lower production of a brain neurotransmitter called orexin. Orexin is key to regulating a number of physiological processes, including hunger and physical activity, and we hypothesize that the obesity and related metabolic function symptoms seen in PWS is linked to a reduction in the levels of orexin in...

Role of fat sensing in the altered feeding behavior and metabolic phenotype of Prader-Willi syndrome

Funded Year: 2022

Our project aims to test the hypothesis that alterations in certain specific lipid sensors and mediators in the hypothalamus may contribute to the disrupted feeding behavior and the altered metabolic phenotype associated with PWS at different stages of postnatal development. These studies will try to reverse the metabolic alterations observed...

Cellular and molecular basis for obesity in PWS

Funded Year: 2022

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

Non-coding RNAs in neuronal differentiation and PWS

Funded Year: 2022

We expect that discovering the direct functions of snoRNAs will uncover new mechanisms – as well as revealing the fundamental basis of PWS. We propose to create a wide picture of RNA-RNA and RNA-protein interactions during the development of brain cells, focusing on interactions of SNORD116, as well as SNORD115 and other ncRNAs synthesized from...

Impairment of neuronal morphology and function in SNORD116 Prader-Willi syndrome mice

Funded Year: 2022

Data from the first year of this project that in the postnatal period mice that lack Snord116 (Snord116del) have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. In the second phase of this project, we will characterize the electrical activity and functional...

Investigation of the Role of Fkbp5 to Induce PWS Phenotypes in a Magel2-null Mouse Model

Funded Year: 2022

With previous FPWR funding, Dr. Yu used advanced, single-cell sequencing to characterize changes in hypothalamic cells in a PWS mouse model and identified activation of a gene important in stress response and energy metabolism, Fkbp5. Here she will test whether inhibiting Fkbp5 rescues deficits in a PWS mouse model.

Prefrontal cortex MC4R neurons as a target for feeding and cognitive symptoms in PWS

Funded Year: 2022

Dr. Ross will investigate how feeding behavior and cognitive flexibility are jointly regulated in the prefrontal cortex of the brain, in neurons expressing MC4R. This study may define a neuronal circuit to target therapeutically.

MC3R inhibition as a therapeutic strategy for treating hyperphagia in Prader-Willi Syndrome

Funded Year: 2022

Dr. Sweeney has shown that the melanocortin 3 receptor (MC3R) is important in regulating food intake and has developed an antagonist of MC3R that inhibits feeding. Here he will test whether inhibition of MC3R decreases food intake in a mouse model of PWS.

How does the epigenetic regulator SMCHD1 regulate the PWS cluster in humans?

Funded Year: 2022

Dr. Blewitt has shown that inhibiting SMCHD1 allows several important protein-coding genes in the PWS to be expressed, but the effect is incomplete. Here she will determine the chromosomal landscape in the PWS region on the maternal chromosome and evaluate how that landscape changes when SMCHD1 is missing, paving the way for more efficient...

MAGEL2 role in adaptive stress response: New insights into MAGEL2 function and pathogenesis of PWS

Funded Year: 2022

Dr. Fon Tacer has been investigating the function of the MAGEL2 protein and believes it plays an important role in how cells adapt to stress. In this study she will explore how cellular stress responses are altered when MAGEL2 is lost.

Where and when does SNORD116 interact with its mRNA targets?

Funded Year: 2022

The Snord116 gene is critical in PWS, but its normal function is incompletely understood. Dr. Good will establish an atlas of where and when the SNORD116 RNA is expressed in the developing mouse brain and how it interacts with one of its putative target genes, Nhlh2, to gain insight into the underlying molecular basis of PWS.

Unraveling the mechanism of PWS by molecular dissection of driver genes in hypothalamic neuron model (Year 2)

Funded Year: 2022

Dr. Derek Tai developed PWS cell lines representing type 1 and 2 deletions and has grown them as 3-D brain organoids, recapitulating the hypothalamus, in a dish. He has applied cutting edge technology to understand how PWS neurons differ from typical neurons and has generated data on gene expression changes. In year 2, he will expand the study to...

Effects of Ultrasound Sensory Neuromodulation in Multiple Mouse Models of Prader-Willi Syndrome

Funded Year: 2022

Dr. Puleo and his team are investigating the use of peripheral ultrasound to modulate targets in the brain and impact energy balance and weight. They have strong preliminary data in several mouse/rat models of obesity and have performed early-stage clinical trials in healthy obese people. Here they will investigate mouse models of PWS to as a...

Impact of Bright Light Therapy on All-Cause Excessive Daytime Sleepiness in Prader-Willi Syndrome

Funded Year: 2022

Dr. Singh and his team will be performing a clinical trial of bright light therapy in children (6-18 years old) with daytime sleepiness, and evaluating the effects on sleepiness, behavior and activity.

Genetic Determinants of Behavioral, Physical, and Physiological Characteristics of PWS

Funded Year: 2022

Differences in PWS symptoms across individuals may be due to variation in genes outside of the PWS critical region. To understand how genetic variants contribute to the severity and complexity of the disease, Dr. Bochukova will analyze variations in the genetic makeup of 160 PWS participants. With support from Soleno Therapeutics, biochemical,...

Optimizing telehealth methods for identifying and treating distress among caregivers of individuals with PWS and WS

Funded Year: 2021

Dr. Kelleher and her group have been developing telehealth-based interventions to improve the mental wellness of those caring for individuals with neurodevelopmental disorders. Here, they will expand an existing caregiver support program (Well-CAST) to families with PWS and another disorder (Williams Syndrome, WS). They will evaluate different...

Planning Proposal to Add Angelman, Prader-Willi and Dup15q Syndromes to the Early Check Newborn Screening Panel

Funded Year: 2021

This study builds on the previous work of Dr. Godler, who developed a high throughput, economical test to detect chromosome 15 disorders in blood spots from newborns. Dr. Wheeler will transfer the technology to a newborn screening program in North Carolina to assess the feasibility of incorporating detection of chromosome 15 disorder into a...

Validation of a promising eye-tracking attentional bias paradigm as a biomarker for satiety in PWS

Funded Year: 2021

Currently, there are no objective biomarkers of hunger/satiety for PWS, which can be a barrier in PWS research. This study aims to develop an objective biomarker for altered satiety and hyperphagia in PWS using an eye-tracking method (measuring where a person is looking) to measure attentional bias (AB; increased attention) to food. Previously,...

Genomewide identification of mRNA sites of 2’-O methylation targeted by SNORD116 snoRNAs (Year 2)

Funded Year: 2021

In PWS, a cluster of small nucleolar RNAs (snoRNAs), the SNORD116 cluster, appears to be of critical importance, but the SNORD116 targets have yet to be identified. Dr. Carmichael and his team have engineered neurons that mimic naturally-occurring PWS deletions and are using them to look for alterations in gene expression and regulation. In year...

Developmental, behavioral, and metabolic characterization of the Necdin/Magel2 double knockout mouse

Funded Year: 2021

PWS is not the result of a single gene mutation but rather is caused by the loss of several contiguous genes, some of which interact with each other. In this project, Drs. Bouret and Muscatelli will study a new mouse model that lacks two PWS genes, Magel2 and Necdin. The goal is to understand how Magel2 and Necdin act together to influence brain...

Miniaturization of the PWS-domain for AAV-based genetic therapy in Prader-Willi syndrome (PWS)

Funded Year: 2021

In this project, Dr. Nicholls will begin studies towards an innovative gene therapy strategy for PWS, by developing a single adeno-associated virus (AAV)-vector that incorporates up to 80% of the PWS genes. This project will generate miniaturized components from the PWS genes and build an AAV vector carrying eight PWS genes. Delivery and...

Elucidating PWS pathophysiology in patient derived 3D human cortical organoids

Funded Year: 2021

In this project Dr. Lodato will use stem cells from PWS patients to generate human 3D cortical organoids (a ‘minibrain in a dish’). Human cortical organoids are valuable models that mimic aspects of human brain development, and analysis of these organoids is expected to shed light on how brain development in PWS differs from that in typical...

Analysis of Delayed Neural Development in PWS DPSC Neurons

Funded Year: 2021

Dr. Reiter’s previous studies suggest that PWS neurons exhibit delayed maturation compared to neurons from typical individuals. Here, his team will use RNA sequencing during neuronal differentiation to better understand the molecular basis of the developmental delay and identify new targets for therapeutic interventions. His team will also...

The role of oxytocin receptor-expressing astrocytes in Schaaf-Yang syndrome and Prader-Willi syndrome

Funded Year: 2021

Prader-Willi (PWS) and Schaaf-Yang syndromes (SYS) are disorders that are both caused by alterations of the MAGEL2 gene, which is either completely missing (PWS) or non-functional (SYS). Working with PWS and SYS mouse models, Dr. Schaaf will investigate the function of a brain ‘support cell’ (astrocytes), which have recently been found to be...

Long Non-Coding RNAs Transcribed From Prader-Willi syndrome Locus: Key Regulators of Gene Expression (Year 2)

Funded Year: 2021

Preliminary research done by Dr. Grzechnik has shown that “long non-coding RNAs”, (lncRNAs) from PWS-region genes may act as important regulators in neurodevelopment. In this project, Dr. Grzechnik will study the changes that occur when the PWS lncRNAs are depleted during the early, middle and late stages of neuronal development.

Gene Therapy of Obesity in Prader-Willi Syndrome by an Autoregulatory BDNF Vector (Year 2)

Funded Year: 2021

Dr. Cao has been developing a gene therapy approach that addresses the major symptoms of PWS, through the delivery of a gene that modulates metabolism and behavior (Brain-derived neurotrophic factor, or BDNF). In her 2nd year of funding, her team will assess whether this single-dose viral gene therapy into brain improves metabolism and behavior...

How is the Epitranscriptomic Signature of Active AGRP Neurons Disrupted in PWS?

Funded Year: 2021

Hyperphagia is thought to be a problem of neurons in the hypothalamus, caused by a dysregulation of neurons that signal being full and being hungry. Disruptions in the code for chemical modifications of RNA (called the epitranscriptome) can have detrimental effects on how neurons function. This project will use human hypothalamic hunger neurons...

Orphan GPCRS and the Neurobiology of Hyperphagia in Prader-Willi Syndrome: Role of GPR160

Funded Year: 2021

A protein called CART controls appetite and body weight in both lean and obese rodents and mutations in the CART gene have been linked to obesity in humans. The protein GPR160 helps CART signal brain cells to control appetite. However, CART and GPR160 have not been studied in PWS before. Therefore, this project will evaluate the role of CART in...

Regulation of PWS Genes in the Endocrine Pancreas

Funded Year: 2021

Pancreatic beta cells produce and secrete two hormones, insulin and amylin, that are important regulators of food intake. These beta cells also express several PWS-region genes, but their function in the pancreas isn’t known. This project will shed light on the role of PWS genes in pancreatic beta cells by studying how PWS genes are regulated in...

Comparative Behavioral and Proteomic Analysis of Rat Snrprn and Magel2 Models

Funded Year: 2021

Two genes disrupted in PWS are SNRPN and MAGEL2, the latter which is the causal gene for Schaaf-Yang syndrome (SYS). The goal of this study is to identify and compare behavioral characteristics and protein profiles of rat models that are deficient for Snrpn and Magel2. These studies will not only provide us a deeper understanding of...

Adult Spine Alignment in Prader-Willi syndrome

Funded Year: 2020

Dr. van Bosse and his team will define the typical posture of grown children and adults with PWS without spinal deformities (e.g., scoliosis). These results will be compared to results from the general population will be used to create guidelines for the alignment of the spine after spinal surgery in children with PWS.

Neurohormonal Controls of Energy Balance in the MAGEL2-Deficient Rat

Funded Year: 2020

Dr. Mietlicki-Baase and her team will investigate neural/neurohormonal control of energy balance in a rat model that lacks Magel2, a gene that is lost or mutated in Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). They will test feeding motivation behaviors and examine the brain areas that control energy balance. They will also...

Role of MAGEL2 in melanocortinergic circuits and feeding regulation

Funded Year: 2020

Dr. Jo and his team are working on appetite-controlling pathways in the brain. Research has shown that mice lacking the Magel2 gene have fewer and less functional proopiomelanocortin (POMC) neurons, which are important in regulating appetite. These neurons appear to work through the amygdala, which is a part of the brain that is important in...

Defining impaired neuronal architecture in the Snord116del mouse model for Prader-Willi Syndrome

Funded Year: 2020

The cognitive challenges experienced by many individuals with PWS remains poorly understood. Pilot data obtained in the Wells laboratory indicates that loss of expression of PWS-region gene, Snord116, leads to reduced length and branching of a certain type of neuron in the cortex of the brain. In this project they will use specialized techniques...

Guanfacine XR for Aggression and Self Injury in PWS A Double Blind Placebo Controlled Trial

Funded Year: 2020

Guanfacine XR (brand name Intuniv) is a medication for ADHD that improves impulse control. Dr. Singh has noted improvements in aggression and self-injury in PWS patients in his practice when using this medication. Here, he will perform a controlled clinical trial to evaluate the efficacy of guanfacine for treating these aspects of PWS, and also...

Unraveling the mechanism of PWS by molecular dissection of driver genes in hypothalamic neuron model

Funded Year: 2020

Dr. Tai and his team have used CRISPR genome editing techniques to generate a series of PWS deletion stem cells (small deletion, large deletion and single genes). Here, they will drive the cells to become hypothalamic neurons in a lab dish, then apply advanced technologies to study the cellular properties of these PWS neurons compared to typical...

Development of a suite of assays for the analysis of PWS patient iPSC-derived cortical neurons

Funded Year: 2020

Dr. Bang and her team will apply a series of ‘assays’ (lab tests evaluating cell function) to PWS patient-specific stem cells (iPSC) that have been driven to become cortical neurons in a lab dish. Once validated, these assays can be used to discover novel therapeutic targets for PWS, screen for drugs that can correct impaired neuronal function,...

A mouse model to assess genetic therapies for Prader-Willi syndrome (Year 2)

Funded Year: 2020

Dr. Resnick and his team have developed a mouse model of PWS that allows precise activation/replacement of the missing PWS genes at different times during development and in different tissues. In this second year of funding, they will work to reestablish gene expression and determine the effects on the potential reversal of traits. This study...

The Role of the Placenta in PWS: Mapping the Expression of PWS Genes

Funded Year: 2020

Dr. Isles and other researchers have shown that abnormal placental function can have profound consequences for brain and behavioral development in the offspring, and that abnormal signaling from the fetal placenta can also have consequences for maternal brain and behavior, which in turn may impact offspring neurodevelopment. This project examines...

Gene Therapy of Obesity in Prader-Willi Syndrome by an Autoregulatory BDNF Vector

Funded Year: 2020

Hyperphagia and the associated metabolic dysregulation is one of the greatest challenges that individuals with PWS and their families face on a daily basis. Dr. Cao has developed a gene therapy that targets the metabolic roots of PWS within the brain’s center for energy regulation. Their group has developed an approach using a single dose of a...

Precise epigenome editing as a novel therapeutic opportunity for Prader-Willi syndrome

Funded Year: 2020

Dr. Mussolino and his team will use a novel approach to activate the maternal genes in the PWS regions. They are developing ‘designer epigenome modifiers’ (A-DEMs), to target key elements of the PWS-critical region on chromosome 15. This approach may allow more specific activation of genes in the PWS region of chromosome 15 for genetic therapy...

Identification of Critical Periods for the Neurodevelopmental and Behavioral Effects of Oxytocin (Year 2)

Funded Year: 2020

The goal of the second year of this research project is to determine, using a preclinical mouse model of PWS, when do the maximal health and biological effects of oxytocin occur (birth, infancy, puberty, or adult life). The study also examines neurological mechanisms by which oxytocin treatment exerts its effects on feeding and behavior in PWS....

Assessment of Epigenetic Driven Circadian Rhythm Defects in Neurons from Individuals with PWS (Year 2)

Funded Year: 2020

Dr. Reiter’s lab looks at stem cell lines from the teeth of PWS subjects to look at the sleep/wake cycle, called the circadian rhythm. People with PWS have a hard time with regulating this cycle. This project will use these stem cell lines to look at the PWS circadian rhythm patterns, as well as changes in DNA that are known to happen at...

The Functional Development of Hunger Neurons in Prader-Willi syndrome (Year 2)

Funded Year: 2020

Dr. Dietrich’s lab has been working on “hunger” neurons, Agrp neurons, that are contained in the hypothalamus in animal brains. They have found that PWS-related genes, particularly Magel2, are enriched in Agrp neurons. In the second year of funding for this study, they will use a mouse model that is missing Magel2 to look at the function of the...

Long Non-Coding RNAs Transcribed From Prader-Willi syndrome Locus: Key Regulators of Gene Expression

Funded Year: 2020

Dr. Grzechnik’s lab is interested in uncovering the biological mechanisms underlying PWS. The deletion in the PWS locus affects the regulation of gene expression in neurons, but scientists are not exactly sure how this mechanism works. This current project is testing how coding and non-coding regions of the human genome are transcribed in cells...

Engineering Epigenome Editing Tools For Sustained Reactivation of Maternal PWS Genes

Funded Year: 2020

Dr. Iglesias has been working on potential genetic therapies for Prader-Willi syndrome and has shown that ‘epigenome editing’ can reactivate the maternal genes in the PWS region in human cells. The current study will focus on determining the molecular requirements to permanently reactivate the maternal genes in the PWS region, so that gene...

Novel Transcriptomic Signatures in Blood and Brain Predictive of Behavioral Issues in PWS

Funded Year: 2020

Dr. Godler’s lab is interested in identifying early predictors of autism and serious mental illness in PWS. In their preliminary data, they have found that inflammatory pathways linked to UBE3A (a key gene that regulates normal brain development and immune cell function) were affected differently in PWS caused by uniparental disomy (UPD),...

Improving Muscle Strength and Muscle Mass in People with Prader-Willi Syndrome

Funded Year: 2019

Neuronal Mechanisms of Developmental Cognitive Impairment in the SNORD116Del Mouse Model for Prader-Willi Syndrome

Funded Year: 2019

In a summer project, a student in Dr. Wells’ laboratory will explore the basis of impaired cognitive ability in a mouse model of PWS. The developmental differences in neurons, specifically examining the dendrites, which are the branches of the nerve cell. Size, shape, and branching of the neurons in PWS mice will be characterized and compared to...

Allele-Specific DNA Replication Timing of the Prader-Willi Locus and its Influence on Neuronal Development

Funded Year: 2019

Dr. Koren studies how DNA is copied (replicates) as cells grow and divide. He previously discovered that the PWS region of chromosome 15 is unique in that the timing of DNA replication on the father’s chromosome is very different than the replication of DNA on the maternal chromosome 15. He hypothesizes that loss of the PWS genes on the father’s...

Role of Central Amygdala Anorexia Neural Circuits in Prader-Willi Syndrome

Funded Year: 2019

This funded project, led by Dr. Cai, will look at the problems in satiety (the feeling of being full) signaling in a mouse model of PWS. Dr. Cai thinks that a specific set of neurons in the amygdala region of the brain do not receive or respond to satiety signals properly, and that is why the appetite suppression in PWS is impaired. He will use...

Role of MAGEL2 in Excitatory Synapse Function

Funded Year: 2019

Dr. Atasoy and his team have recently discovered that the protein Magel2 is important in allowing oxytocin neurons in the brain to communicate normally. These neurons are involved in social behavior, cognition and infant feeding. This funded project will study a mouse model of PWS that is lacking Magel2, to understand how loss of Magel2 impacts...

Investigating the Cause of Mental Illness in PWS Using Magnetic Resonance Spectroscopy (MRS)

Funded Year: 2019

Dr. Holland is a psychiatrist with a long-standing interest in understanding why individuals with PWS are susceptible to mental illness. In this funded project, he will use a brain imaging technique called “magnetic resonance spectroscopy” to look at levels of the neurotransmitter, GABA, in the brain. Dr. Holland thinks that differences in GABA...

Investigation of Rapamycin as a Therapeutic Option in a Mouse Model of Schaaf-Yang Syndrome (SYS)

Funded Year: 2019

Dr. Schaaf and his team have examined a mouse model of Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS), as well as neurons made from skin cells of people with SYS, and have found a significant overactivation of an important cellular pathway called the “mTOR” pathway. There are currently FDA-approved drugs that can reduce the activity...

Evaluating Endosomal Recycling Pathways in Primary Neurons from PWS Individuals (Year 2)

Funded Year: 2019

Dr. Potts and his team have studied cells from PWS ‘baby teeth’ to identify changes in cellular function in PWS. They found that the vesicle recycling is altered in PWS cells, and that this is a consequence of loss of the gene, MAGEL2. They also described that developmental changes in cells from children with PWS compared to typical children. In...

Role of the PWS Gene Magel2 in the Developing Hypothalamus

Funded Year: 2019

Dr. Malcolm Low is an expert in the biology of the nervous system as it relates to appetite. Previously, he has discovered that the Magel2 protein is active in a set of neurons in the brain that regulate appetite. In this project, his team will apply a cutting edge technology, “single cell sequencing”, to determine how these neurons and brain...

Cellular Role of MAGEL2 in Prader-Willi and Schaaf-Yang Syndromes (Year 2)

Funded Year: 2019

In Prader-Willi and Schaaf-Yang syndromes, the MAGEL2 gene is lost or mutated. It is important to understand the normal function of the MAGEL2 gene to better understand what happens when that function is missing. Dr. Rachel Wevrick and her team, in their first year of funding, discovered that MAGEL2 normally works with other proteins that help...

Investigating a New Potential Target for Treatment in Prader-Willi Syndrome

Funded Year: 2019

Dr. Rice and colleagues have shown that there is a decrease in GABA (a compound that helps turn brain activity off) in the brains of individuals with PWS, and this is associated with emotional problems, including a tendency for temper outbursts. In this project, the team will use brain imaging (fMRI) to examine whether a GABA-modulating drug...

Influences of Social Cognition and Reward on ASD Symptoms and Behavior in PWS

Funded Year: 2019

Social cognition, or the ability to understand the thoughts and feelings of others, is impaired in Prader-Willi syndrome. Social reward circuitry (which places value on things in our environment) may also be altered. This impairment may contribute to oppositional behavior and ASD symptoms, which are common in PWS.

A Mouse Model to Assess Genetic Therapies for Prader-Willi Syndrome

Funded Year: 2019

Genetic therapy has the potential to address the root cause of PWS, however, several feasibility questions need to be answered before we can consider genetic therapy for PWS. For example: Does activation of the PWS genes reverse symptoms in models of PWS? Which genes must be turned on? Does gene activation need to occur before a specific age in...

Enhancing Satiation Signaling to Reduce Overeating and Obesity in Prader-Willi Syndrome

Funded Year: 2019

Lack of satiety, or feeling 'full', is a hallmark characteristic of PWS. Satiety mechanisms are not well understood, and it is not clear how the stomach signals the brain to stop eating. It is believed, however, that the vagus nerve to hind brain connection (NTS) may be a key part of this mechanism. In this project, Dr. Edward Fox will...

The Functional Development of Hunger Neurons in Prader-Willi Syndrome

Funded Year: 2019

AgRP ('hunger') neurons are found in the hypothalamus and control feeding, metabolism and compulsive behaviors. There is evidence that AgRP neurons may be overactive during development in PWS, which might lead to some of the characteristics of PWS. In this project, Dr. Dietrich will use a cutting edge technology developed in his lab to evaluate...

CRISPR-mediated molecular dissection of Prader-Willi syndrome

Funded Year: 2019

The PWS region of chromosome 15 consists of several genes. While we know the loss of all these genes together will lead to the characteristics of PWS, we still don’t know exactly what is the contribution of each gene. In this project, Dr Talkowski's team will use CRISPR technology (a very precise way to cut out parts of the genome) to develop...

Genomewide identification of mRNA sites of 2’-O methylation targeted by SNORD116 snoRNAs

Funded Year: 2019

While we know the loss of SNORD116 (a gene that encodes many snoRNA molecules on Chromosome 15) leads to characteristics of PWS, we do not know how this exactly works. We need to understand how SNORD116 functions normally in order to understand why the loss of this region leads to PWS. It is likely that the snoRNAs in the SNORD116 region modify...

Targeting SMCHD1 to address the underlying cause of PWS and SYS

Funded Year: 2019

Associate Professor Blewitt and her research team study how genes shift between ‘sleeping’ to ‘awake’ states, and how this impacts a range of diseases. “A protein called SMCHD1 keeps many genes in their sleeping state,” Associate Professor Blewitt said. “We discovered that SMCHD1’s targets include some of the maternal genes that are involved in...

Assessment of Epigenetic Driven Circadian Rhythm Defects in Neurons from Individuals with PWS

Funded Year: 2018

Dr. Reiter is analyzing neurons, made from stem cells from individuals with PWS. He has noted disruptions in the circadian rhythm of these cells (day/night cycle) that may reflect sleep problems in PWS. His work will identify how the circadian rhythms are disrupted in PWS cells, and pave the way for identifying new drugs to normalize circadian...

Identification of Critical Periods for the Neurodevelopmental and Behavioral Effects of Oxytocin

Funded Year: 2018

This grant supports a new collaboration between two scientists with complimentary expertise. Drs. Sebastian Bouret and Francoise Muscatelli will work to define critical periods for oxytocin use in PWS models, and optimize this therapeutic approach. Mouse models will be used to define the critical period during which oxytocin might provide the...

Understanding the Role of Microglia in the Prader-Willi Hypothalamus

Funded Year: 2018

Dr. Kurrasch is studying whether inflammation in the brain, mediated by special immune cells called microglia, might contribute to hyperphagia and obesity in PWS. Using a mouse model of PWS, she will examine microglia activity and explore whether eliminating microglia improves energy regulation. Funding provided by FPWR – Canada.

Newborn Screening for Prader-Willi and Angelman Syndromes

Funded Year: 2018

Universal newborn screening for PWS will ensure that all babies with PWS are diagnosed at birth. Dr. Godler has developed a sensitive, accurate and cost-effective DNA test for detection of PWS and Angelman syndrome using the bloodspots (“heelprick”) obtained in all newborns. In the study, FPWR is collaborating with with the Angelman Syndrome...

Cannabidivarin (CBDV) vs Placebo in Children with PWS

Funded Year: 2018

This grant will support a small clinical trial evaluating the impact of cannibidiol cannabidivarin (CBDV) on hunger and behavior. CBDV is a compound similar to CBD, but with potential advantages over CBD for PWS. In this study, Dr. Hollander’s group will investigate a form of CBDV, a non-psychoactive drug that has anti-inflammatory,...

Design and Implementation of Hypothalamus-Specific Exosomes to Restore SNORD116 Deletion in PWS

Funded Year: 2018

Dr. Lee’s group is exploring the use of a novel gene transfer vehicle, exosomes, to deliver missing portions of the PWS genes to the hypothalamus. In this pilot study, they seek to develop PWS-specific exosomes and test how well these can deliver genes to neurons and other cells.

Acceptance and Commitment Training (ACT) to Reduce Stress in Fathers of Adolescents with PWS

Funded Year: 2018

Families of those with PWS experience a great deal of stress, particularly during adolescence. In this study, we are funding the development of a new behavioral intervention, aimed at developing more effective coping skills in fathers of adolescents with PWS, as a means to improve overall family well being. Dr. Forster will work with fathers of...

Generation of Non-Human Primate Models of PWS

Funded Year: 2018

This project takes the first steps towards developing a primate (macaque) model of PWS. Animal models of PWS are currently limited and are not able to replicate some important aspects of PWS, such as intellectual disability, as well as behavioral and social impairments. These aspects of PWS may be more effectively studied in a primate model. Our...

Chronic Stress, Cognition, and Food Cue Reactivity in PWS. A Magnetoencephalography Study

Funded Year: 2018

This study will combine advanced brain imaging technology with other assessments to examine how hormonal, cognitive, and psychological factors are interrelated in PWS. Results from this study will increase the understanding of how brain regions involved in food intake are related to appetite hormones, hair cortisol, and neuropsychological...

Cannabinoid-1 Receptor Blockade to Treat Hyperphagia, Obesity and Related Metabolic Disorders in PWS

Funded Year: 2018

This grant supports the development of a new drug to tackle hunger and obesity with PWS. Inversago, a newly started, specialized biotech company, proposes that its CB1 blockers would treat a wider spectrum of symptoms than anything presently in development for PWS. The drug targets the endocannabinoid pathway, which is known to be altered in PWS....

Pig Models of Prader-Willi Syndrome for Pathophysiologic and Therapeutic Interventions

Funded Year: 2018

Overcoming the strong drive to overeat and obesity with negative impacts on life expectancy and life quality is of upmost and crucial importance for individuals with Prader-Willi syndrome (PWS) and their families. Despite advances in understanding the genetic causes of PWS and the establishment of different mouse models that mimic some clinical...

Evaluating endosomal recycling pathways in primary neurons from PWS individuals

Funded Year: 2018

MAGEL2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL2’s link to PWS has been determining its function within cells. Recently, my group has solved this enigmatic question. We...

The gut microbiome in Prader-Willi syndrome

Funded Year: 2018

Prader-Willi syndrome individuals show impaired social behaviors and altered oxytocin levels in the brain, but the reason for this remains unknown. Here we will test whether changes in the gut bacterial content in PWS could perturb social behaviors and related changes in oxytocin. In addition, we will examine whether a probiotic bacteria strain...

The molecular mechanism of SNORD116 action (year 2)

Funded Year: 2018

SNORD116 is a C/D box small nucleolar RNA that is critical for the etiology of PWS, as microdeletions encompassing only SNORD116 cause a PWS-like phenotype. The molecular functions of SNORD116 have been elusive, preventing therapy design. We showed that SNORD116 is not a typical snoRNA, as it associates with different proteins and has a different...

A transcriptome-wide approach to identifying RNA targets of the Prader-Willi locus snoRNAs (year 2)

Funded Year: 2018

Prader-Willi syndrome (PWS) traits are genetically determined by the loss of expression of genes from the paternally inherited small region located on chromosome 15. These genes are transcribed to brain-specific small nucleolar RNAs (snoRNAs) whose function is still unknown. snoRNAs were traditionally assigned a role in ribosomal RNA processing...

Improving social functioning in Prader-willi syndrome (year 2)

Funded Year: 2018

Social isolation and impaired social cognition underpins loneliness, depression and anxiety, contributes to poor health and reduced longevity. They also are associated with such cognitive consequences as impaired executive functioning, cognitive decline, a bias towards negative, depressive thinking, and oversensitivity to perceived social...

Cellular role of MAGEL2 in Prader-Willi and Schaaf-Yang syndromes

Funded Year: 2018

PWS is caused by the loss of function of a set of genes. One of these genes, named MAGEL2, produces a protein that is important for the normal development of the brain, muscles and the endocrine system. Loss of function of MAGEL2 alone causes a disorder that is related to PWS, called Schaaf-Yang syndrome (SYS). To date, researchers have only...

Consequences of targeted SNORD116 deletion in human and mouse neurons

Funded Year: 2018

The role of the brain in controlling food intake is increasingly apparent, with studies finding that genes related to obesity often play a role in brain regions crucial for feeding, appetite, and satiety. Prader-Willi syndrome, one of the most common forms of genetic obesity, results increased food intake (hyperphagia) leading to severe obesity,...

ComuFaces: The perception of communicative faces by infants with Prader-Willi syndrome (year 2)

Funded Year: 2018

Neuropsychological studies have detailed several cognitive deficits in Prader-Willi Syndrome (PWS), among which the observation of altered social interactions, with notable difficulty in interpreting and responding to social information. The integration of the information from the face and the voice is important for our social communication as...

Comufaces: The Perception of Communicative Faces by Infants with PWS (Year 2)

Funded Year: 2018

Neuropsychological studies have detailed several cognitive deficits in Prader-Willi Syndrome (PWS), among which the observation of altered social interactions, with notable difficulty in interpreting and responding to social information. The integration of the information from the face and the voice is important for our social communication as...

Systematic Investigation of Early Social Cognitive Processes and the Feasibility of Intervention

Funded Year: 2017

For Year 1, our project aims were: 1) to characterize the social, cognitive, and affective processes in preschoolers with PWS (by genetic subtype), in comparison to preschoolers with ASD and typically developing children, and 2) to pilot a remotely delivered parent education program to determine if it would be feasible and effective for families...

Neural mechanisms of oxytocin-enhanced infant feeding and social behavior development

Funded Year: 2017

This project uses infant mice to understand the mechanism of a promising treatment for PWS. Oxytocin (OXT) regulates feeding and social behavior. In mouse research and recent clinical trials with infants and young children, OXT seems to improve the core feeding and social behavior disturbances of PWS. In humans, OXT is effective when it is given...

CRISPR-mediated 3D modeling, molecular dissection and epigenetic profiling of PWS

Funded Year: 2017

Deletions on chromosome 15 in the bands labeled 15q11.2-q13 on the chromosome inherited from a subject’s father cause Prader-Willi syndrome (PWS). The unique nature of this causative genetic event has been known for many years, but the precise manner in which it causes the developmental abnormalities of PWS is not completely understood since the...

The SNORD116-NHLH2 pathway: insights into the molecular genetic basis of Prader-Willi Syndrome

Funded Year: 2017

Prader-Willi Syndrome (PWS) is a genetic condition resulting from paternal inheritance of a deletion within an imprinted region of chromosome 15q. The smallest known deleted region encompasses a small nucleolar non-coding RNA locus called SNORD116 (SNORD116), but very little is known about how deletion of SNORD116 leads to PWS. As shown using...

Dissecting a novel brainstem feeding circuit in Prader-Willi syndrome

Funded Year: 2017

There is currently no cure for Prader-Willi syndrome (PWS). PWS is a complex and debilitating disorder that significantly impacts the lives of not only affected patients, but their families, as well. Recent work has revealed a genetic basis for PWS, and a number of the genes affected are known to have unique expression patterns throughout the...

Examination Of Incidence Of Individuals With PWS Undergoing Total Hip and Knee Arthroplasty

Funded Year: 2017

Orthopedic anomalies are common in patients with Prader-Willi syndrome (“PWS”). Surveys suggest that roughly 19% of individuals with PWS may be diagnosed with knock knees, 10% with hip dysplasia, 7% with patellofemoral instability, and 3% with bowlegs. Yet, there is little consensus among orthopedists about how best to address these issues in...

A mindfulness-based intervention for temper outbursts in Prader–Willi syndrome

Funded Year: 2017

Temper outbursts are one of the most commonly reported behavior problems of children, adolescents and adults with PWS. Outbursts cause increased stress for families and costs for the community. Despite this, there is currently no known treatment. Meditation on the Soles of the Feet (SoF) is a mindfulness-based intervention designed specifically to...

Therapeutic Potential of Blocking Zinc Finger Protein 274 Binding to the PWS Locus

Funded Year: 2017

Our goal is to understand the molecular pathways disrupted in Prader-Willi syndrome (PWS) and to develop therapeutic interventions for this disorder. Through the biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that is switched on while the same set of genes on the chromosome 15...

Evaluating factors that may affect the efficacy of intranasal oxytocin treatment in PWS

Funded Year: 2017

Recent studies with oxytocin treatment in PWS have yielded inconsistent results. Intranasal administration of oxytocin by the Toulouse group decreased disruptive behaviors in patients with PWS, but a recent randomized trial in Australia of adolescents and adults of intranasal oxytocin (IN-OT) found no effect on syndrome-specific behavior in...

Gene Expression Analysis in PWS Subject Derived Dental Pulp Stem Cell Neurons (year 2)

Funded Year: 2017

There are two goals to this study: 1) To identify differences between individuals with PWS with autism from those who have PWS without autism using technology that analyzes how genes are expressed and 2) To identify a new role for SNORD115 and SNORD116 which may help explain the PWS condition or how other very small molecules that do not make...

A post-mortem study of von Economo neurons in the frontal cortex of brains of persons with PWS (year 2)

Funded Year: 2017

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Previous neuroanatomical studies in PWS have examined cells in the hypothalamus. To date, no data are available on the cellular structure of the brain in PWS in the frontal lobe where executive function...

Developing objective biomarkers of hyperphagia in children with PWS

Funded Year: 2017

Hyperphagia is one of the distinctive features of Prader-Willi syndrome (PWS), and when not carefully monitored or controlled, can be life threatening. It emerges in early childhood and remains a life-long challenge for individuals with PWS and their caregivers. To effectively manage and, in the future, treat hyperphagia, it is important to be...

Prevalence and aetiology of PWS low level mosaicism in UPD undetected by standard testing

Funded Year: 2017

Prader-Willi syndrome (PWS) is a severe neurodevelopmental disorder found in ~1 in 15,000 to 20,000 births. PWS phenotype caused by the loss of function of several genes located on chromosome 15. These genes are usually ‘switched on’ on the chromosome 15 that is inherited from the father and ‘switched off’ on the chromosome 15 inherited from the...

Role of the endocannabinoid system in PWS-induced osteoporosis and skeletal growth

Funded Year: 2017

Osteoporosis is characterized by weakened and fragile bones and considered one of the major health abnormalities associated with Prader-Willi syndrome (PWS). This problem affects almost 90% of patients with PWS and has a negative impact on their quality of lives by causing physical and functional limitations that could also affect longevity. In...

Transcranial direct current stimulation, startle modulation and event-related potentials of the brain

Funded Year: 2017

Hyperphagia (extreme overeating) is the most significant factor contributing to obesity in Prader-Willi syndrome (PWS) and considered a cardinal feature. PWS is recognized as the most common syndromic cause of life-threating obesity, but no medications are currently available to decrease appetite or lessen obesity in PWS.

Proof of concept study of vagus nerve stimulation from an external device in PWS (year 2)

Funded Year: 2017

The hypothesis set out in our original application is that t-VNS given over time and following a protocol established for its use in epilepsy, will prevent the prolonged and debilitating temper outbursts and associated emotional dysregulation that characteristically affect people with PWS. We further propose that any improvements in behavior are...

Small molecule allosteric modulators of the melanocortin-4 receptor for the treatment of Prader-Willi syndrome

Funded Year: 2016

There is some data suggesting that one of the systems that regulates appetite and weight in the brain, the melanocortin-4 receptor pathway, may be disrupted in PWS. This study will examine a new class of drugs targeting this pathway, in a mouse model of PWS. The drugs will be tested alone and in combination with other drugs currently being...

Physiological and genetic determinants on hyperthermia and hyperphagia in PWS

Funded Year: 2016

Dr. Tucci’s group has shown that mice with the SNORD116 deletion have sleep abnormalities and increased body temperature. They hypothesize that environmental temperature may play a crucial role in the pathophysiology of PWS symptoms including sleep and obesity. They will use PWS mice that will be maintained under different temperature regimens and...

Wake promoting effects of oxytocin

Funded Year: 2016

Caregivers, physicians and patients with PWS report that daytime sleepiness in PWS significantly disrupts daily life. However, the underlying cause of excessive daytime sleepiness in PWS is unknown. Dr. Scammell’s group is exploring the contribution of reduced neuronal function in the hypothalamus region of the brain, specifically, oxytocin/orexin...

Recapitulating obesity and hyperphagia in novel adult-onset mouse models of Snord116 deletion

Funded Year: 2016

Although it is well established that deletion of SNORD116 contributes to PWS in humans, mice missing Snord116 don’t display hyperphagia and obesity. This makes it very difficult to study the biology of SNORD116 and test anti-obesity drugs. In a major breakthrough, Dr. Yeo’s group has shown that if Snord116 is deleted in adult mice, a percentage of...

Improving social functioning in Prader-Willi syndrome

Funded Year: 2016

People with intellectual or developmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for social exclusion and isolation. This underpins loneliness, depression and anxiety, contributes to poor health and reduced longevity. This project will recruit 50 young adults with PWS into an intensive, 10-week group...

Understanding multiple hormone secretion deficits in Prader-Willi Syndrome

Funded Year: 2016

Numerous hormone levels are deficient in PWS. However, the underlying biology and how the altered hormone levels contribute to the characteristics of PWS is not well understood. Dr. Nicholls’ group has developed a novel cell culture model system to study how PWS genes regulate hormone production and release. This model system will advance our...

The molecular mechanism of SNORD116 action and possible SNORD116 substitution strategies

Funded Year: 2016

The loss of two snoRNAs, SNORD115 and SNORD116, plays a central role in the development of Prader-Willi syndrome. However, the normal function of SNORD116 is still unclear, making it difficult to understand what goes wrong when SNORD116 is lost. Dr. Stamm’s group is exploring how SNORD116 influences other genes, and their preliminary studies...

Ghrelin: Is it detrimental, beneficial, or inconsequential in Prader-Willi Syndrome? (year 2)

Funded Year: 2016

Ghrelin levels are elevated in PWS, but why, how, and whether it plays a role in hyperphagia or other aspects of PWS are all still unanswered questions. This project will explore if ghrelin plays a protective role in PWS with regards growth hormone deficiency, hypoglycemia and mental health issues, but a detrimental role with regards to extreme...

Impact of carbohydrate restricted diet upon growth and hyperphagia/food anxiety in children with Prader-Willi syndrome

Funded Year: 2016

Prader-Willi syndrome is a disorder of genetic imprinting characterized by common features including early feeding problems and failure to thrive followed by gradual weight gain and development of hyperphagia. Long-term practice has recommended use of dietary restriction using a variety of approaches for weight control/obesity prevention of...

Preclinical studies of a novel epigenetic therapy for Prader-Willi syndrome

Funded Year: 2016

Despite the significant progress in understanding the molecular basis underlying Prader-Willi syndrome, little advance has been achieved in developing the treatment specifically targeting to the molecular defect. The SNORD116 between the SNRPN and UBE3A genes is important for the major features of PWS. The host transcripts and SNORD116 in the...

Reactivation of the PWS locus via disruption of the ZNF274 silencing complex (year 2)

Funded Year: 2016

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

The MAGEL2 phenotype in comparison to classic Prader-Willi syndrome

Funded Year: 2016

Prader-Willi syndrome (PWS) is a genetically and clinically complex disorder. From a molecular standpoint, a major question has been the contribution of individual genes within the Prader-Willi domain on chromosome 15 to the overall clinical phenotype. Many animal models have attempted to address this question, but have not been able to fully...

Loss of MAGEL2 and hypotonia in Prader-Willi syndrome

Funded Year: 2016

Children with PWS are hypotonic (floppy) at birth. Their poor muscle tone causes delays in sitting and walking and contributes to orthopedic problems such as scoliosis. Reduced endurance lowers the number of calories they can consume per day to manage their body weight, and impairs their quality of life. Treatments that build muscle mass or...

Mitochondrial Complex I dysfunction in Prader Willi Syndrome: A new therapeutic target

Funded Year: 2016

Children with Prader-Willi syndrome suffer from very low muscle tone, growth delay, short stature, developmental delay, muscle weakness and exercise intolerance. Studies have suggested that there is a problem with energy metabolism in PWS but what kind of problem this is and how this leads to PWS is not clear at the present time. Many PWS patients...

A post-mortem study of von Economo neurons in the frontal cortex of brains of persons with PWS

Funded Year: 2016

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Brain difference is the underpinning of the characteristics that define the Prader-Willi personality: food related behaviors, excessive/repetitive behaviors, stress sensitivity/mood disorder, cognitive...

Plastic TASTER: a switching training game for people with PWS that adapts to individual needs (year 2)

Funded Year: 2016

Task switching is a cognitive process important for regulating behaviour. People with PWS generally show impaired switching and this difficulty is linked to people resisting change and showing temper outbursts triggered by changes.

Predictors of psychosis in Prader Willi Syndrome

Funded Year: 2016

There is increasing evidence that Prader-Willi Syndrome is associated with high rates of psychosis, a serious mental disorder that profoundly disrupts thought and emotion. However, little is known about the early or ‘prodromal’ phase of illness and the risk factors that predict the emergence of psychosis in PWS patients. This is a critical gap in...

Oxytocin treatment in Magel2-defcient mice (year 2)

Funded Year: 2016

The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice...

The role of SNORD116 in the neuroendocrine phenotypes of Prader-Willi syndrome

Funded Year: 2016

A hallmark symptom of PWS is extreme, unrelenting hyperphagia associated with obesity. Other medical characteristics of individuals with PWS include low circulating growth hormone, short stature, adrenal insufficiency, hypothyroidism, and hypogonadism. Additionally, individuals with PWS have decreased levels of circulating fasting insulin compared...

Evaluating the Parent-focused Remote Education To Enhance Development (PRETEND) Program in PWS

Funded Year: 2015

This project centers on better understanding the social-cognitive characteristics of Prader-Willi syndrome (PWS) in early childhood and providing education and training to parents of children with PWS to optimize learning and joint engagement between parent and child. There are two goals of this research:

Methylation test validation for combined Prader-Willi and Fragile X syndrome newborn screening

Funded Year: 2015

Activation of silenced genes in Prader-Willi syndrome

Funded Year: 2015

The genetic causes of Prader-Willi syndrome (PWS) are known, including as a complex disorder involving imprinted genes that normally only function after inheritance from the father. A dozen genes contribute to the clinical problems in PWS, although what most of these genes do is poorly understood. Additionally, although numerous mouse models that...

Proof of concept study of vagus nerve stimulation from an external device In Prader Willi Syndrome

Funded Year: 2015

This proposed proof of concept study follows an earlier trial of vagus nerve stimulation, using a surgically implanted medical device, in three people with PWS to investigate whether such treatment might reduce the over-eating behaviour characteristic of people with PWS. Whilst the effects on eating were equivocal, two of the three participants,...

Investigating neural development in an induced pluripotent stem cell model of Prader-Willi Syndrome

Funded Year: 2015

Recent technological developments have ushered in a new era for the medical research field based on our ability to generate stem cells (called induced pluripotent stem cells or iPSCs) out of adult patient cells, such as blood or skin fibroblasts. There are two important benefits of this technology relevant for research into Prader Willi Syndrome...

RNA targets of SNORD116

Funded Year: 2015

Current evidence suggests that most Prader-Willi syndrome (PWS) traits result from loss of paternally inherited SNORD116 gene group. SNORD116 belong to a class of small nucleolar RNAs (snoRNAs), which are involved in modification of other RNA species. snoRNAs act as guides to define sites of target RNA modification by partner enzymes. Typically, a...

Oxytocin and the autonomic nervous system in Prader Willi syndrome

Funded Year: 2015

Study one: There is a reduction in the number of neurons that produce oxytocin in people with PWS. This, along with a range of other evidence supports the likelihood that abnormalities in the oxytocin system are key to the problems of PWS. However, studies examining the levels of oxytocin in PWS as well as clinical trials evaluating the effect...

Gene Expression Analysis in PWS Subject Derived Dental Pulp Stem Cell Neurons

Funded Year: 2015

There are two goals to this study: 1) To identify differences among individuals with PWS and autism from those who have PWS without autism by analyzing gene expression and 2) To identify new patterns of gene expression which may help explain the PWS condition or how other very small molecules that do not make protein (non-coding RNAs) implicated...

Development and validation of ghrelin O-acyltransferase inhibitors for treating hyperphagia in Prader-Willi syndrome

Funded Year: 2015

Obesity and insatiable appetite (hyperphagia) are among the most serious symptoms experienced by Prader-Willi syndrome (PWS) patients. While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in...

Rapamycin treatment to correct the circadian mTOR imbalance in the Snord116 deletion mouse model of PWS

Funded Year: 2015

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis. PWS is an imprinted disorder, meaning that the genes implicated in PWS are expressed only on the paternal but not the maternal chromosome 15q11-13. At the heart of the minimally deleted region in PWS are several processed...

Role of melanin concentrating hormone in an animal model of Prader-Willi Syndrome

Funded Year: 2015

Prader-Willi Syndrome (PWS) is a rare genetic disorder with symptoms that typically include obesity, severe appetite and impaired reproductive function. It is thought that dysfunction of the hypothalamus, a part of the brain that controls body weight and reproduction, underlies some of these symptoms. Our goal is to understand what is...

Characterisation of anti-ghrelin autoantibodies in Prader-Willi Syndrome

Funded Year: 2015

Excessive eating (hyperphagia) is one of the most challenging features of Prader-Willi Syndrome (PWS) and currently there are no medications available for effective appetite regulation. Hyperphagia is most likely to be driven by elevated levels of the appetite-stimulating hormone ghrelin in patients with PWS. The underlying cause of this elevated...

ComuFaces: The perception of communicative faces by infants with Prader-Willi syndrome

Funded Year: 2015

Paying attention to communicative faces is essential for our understanding of the social world. Indeed, faces provide observers rich and complex information about the identity (gender, age, etc), the socio-emotional state (eye-brows movements, eye-gaze) and the linguistic message (auditory speech sounds/mouth movements) of our social partners. The...

Regulation of ghrelin and serotonin receptors by SNORD115

Funded Year: 2015

The loss of two regulatory RNAs is critical for the development of Prader-Willi syndrome. One of these RNAs prevents the formation of a truncated serotonin receptor. We will test the role of this truncated serotonin receptor in the production of growth hormones and determine whether it is a 'master regulator' for other receptors. Based on our...

Biological and molecular functions of PWS-encoded small nucleolar RNA genes

Funded Year: 2015

For several decades the most extensively studied human DNA sequences were those generating messenger RNAs (mRNAs) which are used as templates for protein synthesis. The process decoding the genetic information from mRNAs to proteins is carried out by molecular machines named ribosomes and proteins are commonly perceived as essential molecules...

Reactivation of the PWS locus via disruption of the ZNF274 silencing complex

Funded Year: 2015

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

Ghrelin: Is it detrimental, beneficial, or inconsequential in Prader-Willi Syndrome?

Funded Year: 2015

Plasma levels of the peptide hormone ghrelin are markedly elevated in individuals with Prader-Willi Syndrome (PWS), however the functional consequences of this elevation have not yet been determined, nor are the mechanistic causes of ghrelin elevation known. Many attribute the characteristic, maladaptive PWS eating behaviors directly to ghrelin,...

Linking the cellular function of MAGEL-2 to its role in PWS

Funded Year: 2015

Background: MAGEL-2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL-2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL-2’s link to PWS has been determining its function within cells. Recently, my group has solved this...

Mechanisms of sleepiness and other sleep abnormalities in a mouse model of Prader-Willi Syndrome

Funded Year: 2015

Many individuals with PWS have sleepiness, abnormal rapid eye movement (REM) sleep, and falling episodes resembling cataplexy - episodes of muscle paralysis that are usually triggered by strong, positive emotions. Caregivers, physicians and patients with PWS report significant disruption of daily life as a result of these sleep-related symptoms....

Small molecules and therapeutic potential for PWS

Funded Year: 2014

A publication resulting from this project was highlighted in an FPWR Research Blog post “Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome” (December 2016)

The role of SNORD116 in Prader-Willi syndrome (year 2)

Funded Year: 2014

Prader-Willi syndrome (PWS) is caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Training task switching to decrease temper outbursts in people with PWS

Funded Year: 2014

Temper outbursts are commonly shown by people with Prader-Willi syndrome (PWS) and can cause great problems for people with the syndrome, their family members and caregivers. One common reason for temper outbursts is that people with PWS find changes to routines or to plans very difficult. This difficulty with change is linked to impairment in a...

Role of the lipid-derived satiety factor, oleoylethanolamide, in PWS

Funded Year: 2014

Prader-Willi Syndrome (PWS) is a complex genetic disorder characterized by an insatiable feeling of hunger and an irrepressible urge to overeat. If left uncontrolled, hunger and overeating can lead to morbid obesity, diabetes, cardiovascular disease and premature death. Why PWS causes hunger is an important question that must be answered in we...

Genome-wide survey of DNA methylation in PWS

Funded Year: 2014

Prader-Willi syndrome (PWS) is a rare genomic imprinting disorder caused by an abnormality in the PWS critical region (PWSCR), a particular region of 15th chromosome (15q11-q13). Genomic imprinting refers to a phenomenon in which genes from specific parent can be expressed. PWSCR contains several imprinted genes that are only expressed from either...

Development of appetite-related neural circuits in a mouse model for PWS (year 2)

Funded Year: 2014

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety or behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

The role of PREPL in the pathophysiology of PWS: evaluation of a novel therapeutic approach for the treatment of hypotonia

Funded Year: 2014

A remarkable clinical resemblance between Prader-Willi syndrome (PWS) and hypotonia-cystinuria syndrome (HCS) was observed in our multidisciplinary clinic for PWS in our center. All HCS patients were initially referred for genetic analysis of PWS. Patients with either syndrome suffer from weakness and poor sucking in the newborn period. This...

Evaluation of autism-like behaviors in mice deficient for Magel2

Funded Year: 2014

MAGEL2 is one of five genes in the Prader-Willi syndrome (PWS) critical domain on chromosome 15 that encodes a protein. Our group recently described a group of patients with mutations of MAGEL2 causing Prader-Willi features and autism. Autism spectrum disorder is seen in up to one third of individuals with PWS, and in all individuals with MAGEL2...

Nutritional aspects of PWS and childhood obesity: a metabolomics approach

Funded Year: 2014

In Prader-Willi syndrome (PWS) the progression from poor appetite and failure-to-thrive (FTT) to obesity and voracious appetite is complex and takes several years. We have recently shown that there are 6 distinct post-natal nutritional phases in PWS. By looking at the end products of cellular processes in individuals with PWS before and after the...

Transcranial direct current stimulation, startle modulation and event-related potential of the brain to evaluate hyperphagia in PWS

Funded Year: 2014

Hyperphagia (extreme overeating) is the most significant factor contributing to obesity in Prader-Willi syndrome (PWS) and considered a cardinal feature. PWS is recognized as the most common syndromic cause of life-threating obesity, but no medications are currently available to decrease appetite or lessen obesity in PWS. Preliminary studies have...

Gut microbiome in individuals with PWS

Funded Year: 2014

Prader-willi syndrome is a genetic disorder caused by loss of a portion of a copy of chromosome 15. Common features include early problems with muscle weakness and feeding followed by occult weight gain without an increase in food consumption beginning during late infancy/early toddler period prior to the onset of hyperphagia. Recent research has...

How does oxytocin cure early feeding and adult social behavior alterations in Magel2 deficient mice, a model for the PWS?

Funded Year: 2014

The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice...

Comprehensive behavioral informatics approach to CNS function in PWS mouse models

Funded Year: 2014

The identification of genetic loci conferring susceptibility to Prader-Willi Syndrome (PWS) provides valuable opportunities for understanding its biological basis. A powerful approach for probing the roles of genes within the nervous system is to introduce them into mice. The resulting mouse models may be studied in depth to determine how genes...

Inhibitory circuits and transmission in the hypothalamus in a mouse model of PWS

Funded Year: 2014

The genetic disorder Prader-Willi syndrome (PWS), results in debilitating physical, endocrine, cognitive, and behavioral symptoms. Many of the characteristics of PWS, such as uncontrollable food intake, stunted growth, and emotional problems suggest that disruptions in brain regions such as the hypothalamus may cause this. Recently, the gene...

Injectable protein gene activation therapy for PWS (year 2)

Funded Year: 2014

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human chromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Unraveling the developmental neurobiology of PWS: a cross-sectional brain-imaging study (year 2)

Funded Year: 2014

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at a high risk of developing psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging study in...

A Dose Titration Study of Diazoxide Choline Controlled-Release Tablet (DCCR) in Patients with Prader-Willi syndrome with a Double-Blind, Placebo-Controlled, Randomized Withdrawal Extension

Funded Year: 2014

Once Prader-Willi patients reach the stage where hyperphagia is a dominant characteristic of the disease, the progression to obesity, morbid obesity and diabetes and their complications reduces the quality of life of the patient and increases their risk of death from a number of causes. The constant food seeking and food obsession combined with...

Investing in Young Investigators

Funded Year: 2014

Ariana Garagozzo is not just a future scientist; she is also the sibling of a young man with Prader-Willi syndrome. As an undergraduate student at Dickinson College, Ariana’s passion to find a cure for hyperphagia has clearly defined her path towards a medical career in PWS research!

The role of SNORD116 in Prader-Willi syndrome

Funded Year: 2013

Prader-Willi syndrome (PWS) is caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Investigation of ghrelin-o-acyltransferase as a target for treating hyperphagia in Prader-Willi syndrome (Year 1)

Funded Year: 2013

Obesity and insatiable appetite (hyperphagia) are among the most serious symptoms experienced by Prader-Willi syndrome (PWS) patients. While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in...

Oxytocin vs. placebo for the treatment of hyperphagia in Prader-Willi syndrome

Funded Year: 2013

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of inherited genes from fathers on chromosome 15. PWS is characterized by intellectual disabilities, repetitive and compulsive behaviors, social cognition deficits, increased eating and obesity. These individuals typically consume up to three times the normal caloric...

Support to develop a grant application for a cross-over controlled trial of vagus nerve stimulation (VNS) in PWS

Funded Year: 2013

The vagus nerve is a major route of communication between the brain and the gut. Vagus nerve stimulation (VNS) is a procedure whereby a small implanted device placed under the skin on a patient’s chest delivers an intermittent electrical impulse to the vagus nerve, which will travel up and down the nerve and into the brain and to the gut. VNS has...

Clinical trials initiative

Funded Year: 2013

Dr. Jennifer Miller is assisting FPWR in identifying opportunities for clinical trials in PWS and developing recommendations for the conduct of such clinical trials. Among the issues to be addressed are target population, identification of informative surrogate endpoints, and assessment of recruitment challenges. In addition, she is providing...

Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome (year 2)

Funded Year: 2013

This supplement will help Dr. M. Tauber complete the study awarded in 2011: Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome. Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe disabilities such as morbid obesity, as well as behavioral and socialization problems. We are...

European PWS blood bank coordinator

Funded Year: 2013

Dr. Tauber is leading a European effort to collect blood samples on infants and children with PWS to monitor changes in hormones over time. This funding will support a blood bank recruitment coordinator, who will work to collect clinical data on birth, growth, endocrine functions and feeding behavior in newly diagnosed patients with PWS.

Understanding the Neurobiology of Temper Outburst Behaviors in Prader-Willi Syndrome

Funded Year: 2013

Understanding temper outbursts are a significant challenge in PWS, and little is known about why they happen so frequently. The investigators will use brain imaging to better understand GABA receptor activation across brain regions in times of frustration for those with PWS. Research Outcomes: Publications The characteristics of temper outbursts...

Establishment of an in vitro model of muscle cells derived from primary fibroblasts to study dysregulation of translational capacity in PWS

Funded Year: 2013

Previous results showed that our physical rehabilitation program could induce weight loss in a group of adult PWS patients, but failed to improve their muscular mass (Grolla et al.2010). The loss of muscle mass affects elderly, obese and PWS patients leading to frailty and impaired quality of life. It is becoming apparent, using animal models,...

Hypoglycemia in PWS: A prospective study

Funded Year: 2013

Prader-Willi Syndrome (PWS) is a complex genetic disorder associated with varied clinical findings, neurocognitive delay, and endocrine abnormalities. Clinically, individuals with PWS progress along a path marked by different nutritional stages. In infancy, children with PWS have hypotonia, poor feeding, excessive daytime sleepiness, and...

Neurobiology of temper outburst behaviours in Prader-Willi syndrome - imaging pilot study

Funded Year: 2013

Individuals with Prader Willi Syndrome (PWS) are known to display frequent and severe temper outburst behaviours throughout their life. These behaviours can have a significant impact on the quality of life for the individual and their family. Prader Willi outbursts are reactive explosion of emotion that once provoked the individual has little...

Oxytocin actions of prefrontal cortex circuits in a mouse model of Prader-Willi Syndrome

Funded Year: 2013

Mental illness is a major problem in Prader-Willi syndrome (PWS). It prevents social interactions and seriously threatens the quality of life of the patient and of those around the patient. Mood swings, stereotyped repetitive behaviors, psychotic episodes are dependent on proper functioning of brain regions such as the prefrontal cortex. Activity...

Unraveling the developmental neurobiology of PWS: a cross-sectional brain imaging study

Funded Year: 2013

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at very high risk of developing severe psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging...

Functional Assessment of snoRNA derived microRNAs in Prader-Willi Syndrome

Funded Year: 2013

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder, predominantly caused by a deletion on the long arm of chromosome 15. This deletion eliminates a group of genes called HBII-85 whose function is currently unknown. Therefore, this proposal aims to investigate the underlaying molecular mechanisms behind the loss of HBII-85 and how this...

Targeting the peripheral endocanniabinoid system for the treatment of obesity in a mouse model of PWS

Funded Year: 2013

Extreme obesity is one of the major health problems related to Prader-Willi syndrome (PWS), yet there are few effective medications. Endocannabinoids (eCBs) are lipid signaling molecules that act on a cellular receptor, called the CB1 receptor. This receptor is present in the brain and in peripheral tissues, where it also recognizes the...

Osteoporosis in individuals with PWS and the role of vitamin D receptor

Funded Year: 2013

Prader-Willi syndrome is a multisystem disorder due to absence of paternally expressed imprinted genes at 15q11.2-q13. Diminished bone mineral density (BMD) and osteoporosis are common in PWS individuals, especially in adolescence and adulthood. The reasons for the increased prevalence of osteoporosis in PWS are not totally clear, but decreased...

Evidence based approach to dietary management of PWS

Funded Year: 2013

: Prader-Willi Syndrome (PWS) is a genetic disease characterized by failure to thrive and low muscle tone during infancy, followed by food-seeking, insatiable appetite and progressive obesity in childhood. The resulting increases in total body fat and decreases in muscle mass lead to metabolic problems such as diabetes and heart disease.

Allele specific regulation of SNORD116 in PWS

Funded Year: 2013

Prader-Willi Syndrome (PWS), a complex genetic disorder that results from a failure to inherit a normal copy of the father’s chromosome 15. Key genes on the paternal chromosome are deleted, but how the deletion of this region leads to PWS is a complete mystery. In PWS, a normal copy of the mother’s chromosome 15 is inherited, but the genes are...

The role of the prefrontal cortex in PWS hyperphagia

Funded Year: 2013

Among the many complications of Prader-Willi Syndrome (PWS), the increased food intake (hyperphagia) has serious long-term medical consequences. The goal of this proposal is to define novel brain regions that may contribute to this problem. Studies of brain activity suggest that the prefrontal cortex might be different in PWS patients. This is an...

Development of appetite-related neural circuits in a mouse model for Prader-Willi syndrome (year 1)

Funded Year: 2013

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety of behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

Pancreatic and neuro-endocrine cell secretory pathway deficits in PWS

Funded Year: 2013

Many advances in recent years have added to our understanding of the genetic causes of PWS, including recognition of it as a disorder of genomic imprinting involving defective genes that normally only function after inheritance from the father. At least a dozen genes appear to contribute to the many clinical problems seen in PWS. Unfortunately the...

Use of stem cell-derived neurons to identify the molecular basis of the PWS

Funded Year: 2013

Prader-Willi syndrome (PWS) is caused by a loss of expression of specific genes normally expressed only from paternal alleles on chromosome 15. PWS patients display common symptoms, which include feeding difficulties in infancy, loss of muscle tone, rapid weight gain after two years of age, extreme hunger and unrelenting appetite, obesity, and...

Reactivation of maternally-silenced genes in PWS

Funded Year: 2013

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human cromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Small molecular screening and therapeutic potential for PWS

Funded Year: 2013

Like most genetic disorders, there is no specific therapeutic intervention targeted to the molecular defect for Prader-Willi syndrome (PWS). The clinical presentations of PWS are caused by paternal deficiency of genes in the chromosome 15q11-q13 region. Recent reports indicate a region between the SNRPN and UBE3A genes harboring SnoRNA clusters is...

Development of leptin dysregulation in a mouse model of obesity in PWS

Funded Year: 2013

The brain balances energy stores with energy expenditure with little conscious effort. The hypothalamus is a part of the brain that senses levels of a hormone called leptin, which is produced by fat. Excess leptin normally causes a decrease in appetite and increase in activity. This balance is disrupted in obese children who carry mutations in...

Nutritional aspects of Prader-Willi syndrome and childhood obesity: correlation of plasma orexin levels with nutritional phases

Funded Year: 2013

Early in infancy, babies with Prader-Willi syndrome (PWS) have no interest in feeding manifested by lack of crying for food and failure-to-thrive requiring assisted feeding with a G-tube, NG tube, or cross-cutting of bottle nipple (phase 1a). There is then a series of transition through five nutritional phases, ending in the classic PWS...

Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome

Funded Year: 2012

Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe disabilities such as morbid obesity, as well as behavioral and socialization problems. We are greatly lacking in information on the natural history of this complex disease and the factors involved in its progression and outcome. Early diagnosis and a...

Role of SNORD116/HBII-85 snoRNAs in Prader-Willi syndrome

Funded Year: 2011

Although the genetic region on chromosome 15 that is responsible for Prader-Willi Syndrome (PWS) has been known for many years, how the gene or genes within this large region cause the complex clinical features of PWS is still unknown. We have identified a small deletion on chromosome 15 of a patient with PWS features that narrows the causative...

Environmental, physiological and neural bases of skin picking in Prader-Willi syndrome

Funded Year: 2011

Many people with Prader-Willi Syndrome (PWS) frequently engage in severe skin picking behavior, often causing open wounds and sores that can become infected. Why do people with PWS do this? How often and under what circumstances does it occur? Are people with PWS more likely to exhibit skin picking when they are bored or anxious? Does the skin...

Generating a novel model of ghrelin-null Prader-Willi syndrome

Funded Year: 2011

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a lack of muscle tone at birth, a failure to thrive in infancy, and mild learning disabilities. On emerging from infancy, children with PWS show reduced skeletal growth and an insatiable appetite, which, when combined with an obsession with food, results in obesity....

A Prader-Willi syndrome mouse model with brain specific ablation of snoRNA clusters from the Snrpn to Ube3a region

Funded Year: 2011

Two lines of evidence are promoted this proposal. First, recently, smaller microdeletions in the region between the human SNRPN and UBE3A genes have been reported in several cases with features consistent with PWS, including childhood obesity, hyperphagia, and hypogonadism. Second, interestingly, recent studies of genomewide survey of imprinting...

A pig model of PWS: a breakthrough for obesity, clinical and therapeutic studies

Funded Year: 2011

Overcoming the severe drive to overeat and obesity that provides the greatest threat to life expectancy and life quality is of upmost and crucial importance for PWS individuals and families. Despite advances in understanding the genetic causes of PWS and the establishment of different mouse models that mimic some clinical components, the...

Longitudinal investigation of pubertal development and reproductive hormones in Prader-Willi syndrome from infancy through adulthood (year 2)

Funded Year: 2011

Background: Hypogonadism (impaired sex hormone production) is a major feature of PWS, although the clinical expression is variable. Nevertheless, early onset of puberty has been seen in both sexes, and pregnancies have been documented in some PWS women. The causes of hypogonadism in PWS are heterogeneous, encompassing a spectrum which includes...

Role of Kiss1 neurons in mediating grhrelin’s effect on effect on reproduction and metabolism (year 2)

Funded Year: 2011

Prader-Willi syndrome (PWS) is a genetic disorder characterized by impairment of a myriad of physiological systems including growth, development, metabolism and reproduction. Although the physiological deficits observed in individuals with PWS come to be well-recognized, the mechanisms and/or cause for the generation of these characteristics are...

Mechanism of hyperphagia and therapeutic interventions in mouse models for Prader-Willi syndrome

Funded Year: 2011

The overall goals of our research are to elucidate the pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS, and to evaluate two types of treatments for persistent hunger and food seeking behavior. We have focused on the role of a special type of RNA, called Snord116 (formally PWCR1/HBII-85) small nucleolar RNA...

Characterization of skeletal muscle abnormalities in mouse models of Prader-Willi syndrome: Functional role of Necdin?

Funded Year: 2011

One of the major clinical problems of patients with PWS is decreased muscle tone and muscle weakness leading to delayed gross motor milestones and additional clinical problems (e.g. scoliosis) later in life. Interestingly, there is significant lack of knowledge regarding the underlying abnormalities of skeletal Muscle in patients with PWS, nor is...

R-loop formation and chromatin decondensation at the PWS critical locus

Funded Year: 2011

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology but a complex epigenetic basis. PWS is an imprinted disorder, meaning that genes expressed only on the paternal but not the maternal chromosome 15 are responsible. Furthermore, unlike genetic mutations that affect protein-coding genes, the smallest genetic...

Derivation of live Prader-Willi syndrome neurons from induced pluripotent stem (iPS) cells

Funded Year: 2010

A better understanding of the causes of Prader-Willi syndrome (PWS) and the discovery of potential therapies has been hampered by the unavailability of live tissues. In our laboratory (Marc Lalande), we have established induced pluripotent stem cell (iPSC) technology to create models of human disease in a test tube/tissue culture dish. Skin cells...

Longitudinal study of reproductive hormones in Prader-Willi syndrome from infancy through adulthood

Funded Year: 2010

Hypogonadism (decreased production of testicular or ovarian hormones resulting in incomplete sexual development) is considered to be a cardinal feature of Prader-Willi syndrome, however, the clinical expression is variable. Most, but not all PWS males have unilateral or bilateral undescended testes. Arrested pubertal development leads to...

The relationship between serum brain-derived neurotrophic factor (BDNF) levels, BDNF haplotypes and neurocognitive performance in children with PWS

Funded Year: 2010

Prader-Willi Syndrome (PWS) is a genetic disease characterized by failure to thrive and low muscle tone during infancy, followed by food-seeking and severe obesity in childhood. Other manifestations include altered pain perception, cognitive impairment, maladaptive behaviors (obsessive compulsive, temper tantrums, skin picking, rigid thinking and...

MCH neurons in animal models of Prader-Willi syndrome

Funded Year: 2010

Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to "floppy" infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown that...

Role of Kiss1 neurons in mediating ghrelin’s effect on reproduction and metabolism (year 1)

Funded Year: 2010

Prader-Willi syndrome (PWS) is a genetic disorder characterized by impairment of a myriad of physiological systems including growth, development, metabolism and reproduction. Although the physiological deficits observed in individuals with PWS come to be well-recognized, the mechanisms and/or cause for the generation of these characteristics are...

The 5-HT2CR: Mining a new experimental approach to therapeutics for Prader-Willi syndrome

Funded Year: 2010

Prader-Willi Syndrome (PWS) is a complex genetic disorder in which several genes are missing or not functional. PWS is characterized by initial loss of muscle tone and failure to thrive neonatally; children with PWS develop behavioral and cognitive problems, reproductive defects, and excessive overeating. A major medical concern is the morbid...

Plasma oxytocin and other appetite-regulating hormones in Prader-Willi syndrome before and after treatment with intranasal oxytocin

Funded Year: 2009

Prader Willi Syndrome is characterized by a range of well-recognised symptoms including overeating and other food obsessions, rage attacks or tantrums, skin-picking, obsessions, abnormalities of sleep breathing and body temperature, and diificulties in learning and understanding social cues. These difficulties have serious impacts on the health of...

Exenatide: A potential treatment for hyperphagia and obesity in persons with Prader-Willi syndrome

Funded Year: 2009

Prader-Willi Syndrome (PWS) is a condition characterized by growth hormone deficiency, hypogonadism, various behavioral disturbances, an insatiable hunger drive (hyperphagia) and excessive eating leading to life-threatening obesity. The specific causes of the disturbed eating behavior in persons with PWS remain unknown. More importantly, effective...

Identification of substances that substitute for the loss of snoRNAs from the Prader-Willi critical region

Funded Year: 2009

Genetic studies strongly indicate that the Prader-Willi syndrome is caused by the loss of small nucleolar RNAs (snoRNA). SnoRNAs are short RNAs that do not encode a protein. In most cases studied, snoRNAs help in the modification of other RNAs. However, the function of the snoRNAs missing in people with Prader-Willi syndrome is not clear. In...

Role of the HBII-85 snoRNA cluster in the pathogenesis of PWS

Funded Year: 2009

It has been known for many years that loss of function of the copy of the DNA inherited from the father for genes in the Prader-Willi syndrome (PWS) region cause PWS. However, there are multiple genes in the region, and it has not been clear as to exactly which gene or genes cause PWS. Based on studies of a series of rare families with...

An improved mouse model of Prader-Willi syndrome (year 2)

Funded Year: 2009

Infants with Prader-Willi syndrome (PWS) often suffer failure to thrive that gives way to obesity and excessive eating (hyperphagia) during early childhood. The syndrome is due to the absence of several genes on chromosome 15. Animal models can be used to investigate the etiology of the syndrome and to test potential therapies. Several mutations...

R Loop structures maintain epigenetic imprints at the Prader-Willi Imprinting Center (year 2)

Funded Year: 2009

At the genetic level, Prader-Willi syndrome (PWS) is due to the lack of expression of a specific portion of chromosome 15. This portion contains genes that, in normal circumstances, are only active on the paternally inherited chromosome. Indeed, the corresponding genes on the maternally inherited chromosome are silenced – a phenomenon called...

Hypocretin/orexin deficiency in Prader-Willi syndrome animal models

Funded Year: 2009

The Prader-Willi syndrome (PWS) is a disease caused by mutations on human chromosome 15 leading to "floppy" infants initially, and obesity and sleep disorders later. Although genetic defects underlying PWS have been documented, it is still not well understood how the loss-of-function of genes results in various symptoms in PWS. It has been shown...

Regulation of expression of Prader-Willi syndrome region genes in the hypothalamus by nutritional and hormonal signals

Funded Year: 2009

The cause of the severe obesity characteristic of patients with Prader-Willi syndrome (PWS) is unknown. In the past few years however, there has been an explosion of information regarding the factors involved in the control of bodyweight. In particular, the hormone leptin, which is produced by fat, and a group of molecules in the brain called the...

Ghrelin and peptide YY levels and gene expression in Prader-Willi syndrome

Funded Year: 2009

Prader-Willi syndrome (PWS) is a complex genetic condition due to imprinting or the differential expression of genetic information depending on the parent of origin. The majority of subjects with PWS have a deletion of chromosome 15q11-q13 region received from the father while others have maternal disomy 15 (both 15s from the mother) or a mutation...

Understanding the action of ghrelin in the brain: Identification of novel treatments for hyperghrelinaemia

Funded Year: 2009

(Year 2 of this project)

Understanding the action of ghrelin in the brain: Identification of novel targets for hyperghrelinemia

Funded Year: 2009

In patients suffering Prader-Willi syndrome it has been shown that there is a greatly elevated level of a hormone known as ghrelin. This hormone is known to normally stimulate hunger and food intake. However, the levels of the circulating hormone leptin that signals the need to reduce food intake and increase energy expenditure is not similarly up...

The sympathetic and enteric nervous systems in necdin-null mice

Funded Year: 2009

Background The automatic nervous system performs many functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection and together with the autonomic system of the brain, emotion and other complex behaviors. The cells (neurons) of the autonomic nervous system extend...

The role of the midbrain dopaminergic reward circuitry in ghrelin's effects on food intake and body weight

Funded Year: 2009

Prader-Willi Syndrome is a disorder characterized by numerous medical conditions, including excessive eating, low metabolic rate, growth hormone deficiency, hypogonadism and various cognitive deficits. In fact, obese individuals with PWS are described as having a nearly constant state of hunger, which manifests in various maladaptive feeding...

The orexin system in Prader-Willi syndrome

Funded Year: 2009

Prader-Willi syndrome (PWS) is a genetic disorder characterized by a number of clinical features, including short stature, poor muscle development, excessive appetite with progressive obesity, mental retardation, behavioural abnormalities and sleep disturbances. Obesity occurs in over 90% of affected individuals and is the most prominent physical...

Synaptology in Prader-Willi syndrome

Funded Year: 2009

Human behavior is determined by the brain. The function of the brain relies on connections between various types of neurons. The main form of communication between neurons is via the so called synapses. The number and type of synapses between neurons are determinants of behavior. Thus, we hypothesize that altered behavior in people with PWS is due...

snoRNAs located in the PWS critical region regulate alternative splicing of pre-mRNAs

Funded Year: 2009

Prader Willi syndrome is caused by the loss of gene expression from a known region in the human genome. In almost all genetic diseases studied, the loss of gene expression results in a loss of a certain protein, since ultimately proteins are made from genes. One problem in understanding the Prader-Willi syndrome is that only a few proteins are...

Role of PWCR1 snoRNAs in Prader-Willi Syndrome

Funded Year: 2009

The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We have focused on the role of a special type of RNA, called PWCR1/HBII85 small nucleolar RNA (snoRNA), that was discovered in our laboratory. Studies of rare cases of PWS with smaller deletions and...

PYY 3-36 and PP: Potential targets for co-treatment against hyperphagia and obesity

Funded Year: 2009

An insatiable appetite (hyperphagia), in conjunction with a low metabolic rate, means that obesity and all of its associated health risks are common in people with Prader-Willi syndrome. Overeating is one of the main barriers to independent living in adults with PWS. Moreover, attempts to control their food intake often lead to exacerbation of...

PWS mouse model with deleted snoRNA cluster

Funded Year: 2009

The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We believe that a detailed level of understanding is necessary to design rational interventions. Recently, our laboratory has focused on the role of a special type of RNA, called PWCR1/HBII-85 small...

Exploring the potential of using demethylation drugs to treat PWS

Funded Year: 2009

More than 95% of Prader-Willi syndrome (PWS) cases are caused by either a large deletion of paternal chromosome 15q11-q13 or maternal uniparental disomy (UPD) of chromosome 15. The major gene or genes responsible for PWS are subject to genomic imprinting and exclusively expressed from paternal chromosome. For patients with a large chromosomal...

Evaluation of sensory processing in individuals with PWS

Funded Year: 2009

Individuals with Prader-Willi Syndrome (PWS) have been described by parents and clinicians as having difficulty with regulation of sensory stimuli from the environment. It is suspected that this problem may be related to other symptoms of PWS such as poor satiety recognition, decreased sensitivity to pain, tendency to self-injure and sleep issues....

Endocrine and molecular basis for Prader-Willi syndrome

Funded Year: 2009

Despite years of study, we do not yet know the basis of Prader-Willi syndrome (PWS), either the roles of the genes defective in PWS or the basis of the clinical features. Many people think the hypothalamus, a small brain region controlling appetite and many endocrine functions is solely responsible, yet this may not be the single cause and using a...

The effect of growth hormone replacement therapy on physical and behavioral sexual development in persons with PWS

Funded Year: 2009

This study examines the effect of growth hormone replacement therapy (GHRT) on physical and behavioral sexual maturation in males and females with Prader-Willi syndrome (PWS). Previously, sexual maturity among affected individuals has been largely ignored due in part to the assumed universality of underdeveloped/immature genitals, lack of sex...

Activation of the maternal allele at the PWS/AS domain as a potential therapeutic approach (year 1)

Funded Year: 2009

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....

The risk of early onset Alzheimer's disease in Prader-Willi syndrome

Funded Year: 2009

Alzheimer's disease (AD) is well-known as a condition of old age, prevalence rising with age from about 70 years. However, some groups appear to be at risk from a much earlier age, for example people with Down's syndrome. Recently, in pathological studies of people with Prader-Willi syndrome (PWS) who died aged over 40 years, signs of AD have been...

The effect of growth hormone replacement therapy on physical and behavioral sexual development in persons with PWS

Funded Year: 2009

This is Year 2 of a study to examine the effect of growth hormone replacement therapy (GHRT) on physical and behavioral sexual maturation in males and females with Prader-Willi syndrome (PWS). Previously, sexual maturity among affected individuals has been largely ignored due in part to the assumed universality of underdeveloped/immature genitals,...

R-Loop structures maintain epigenetic imprints at the Prader-Willi imprinting center

Funded Year: 2009

At the genetic level, Prader-Willi syndrome (PWS) is due to the lack of expression of a specific portion of chromosome 15. This portion contains genes that, in normal circumstances, are only active on the paternally inherited chromosome. Indeed, the corresponding genes on the maternally inherited chromosome are silenced – a phenomenon called...

PYY and PP: Potential targets for co-treatment against hyperphagia and obesity

Funded Year: 2009

An insatiable appetite (hyperphagia), in conjunction with a low metabolic rate, means that obesity and all of its associated health risks are common in people with Prader-Willi syndrome. Overeating is one of the main barriers to independent living I adults with Prader-Willi syndrome. Moreover, attempts to control their food intake often lead to...

Linking learning with neurodevelopmental functioning: Management strategies for children with Prader-Willi syndrome

Funded Year: 2009

Children with Prader-Willi syndrome (PWS) exhibit wide variation in their behavior and educational profiles, which has made the development of effective teaching strategies difficult for many educators. The proposed study would attempt to remedy this problem through the development of rating forms that would provide specific, detailed information...

Exploring the potential mitochondrial dysfunction in mouse models of Prader-Willi syndrome

Funded Year: 2009

Prader-Willi syndrome (PWS), a genetic, metabolic and behavioral disorder, is caused by paternal deficiency for human chromosome 15. Clinic presentations include infantile hypotonia, difficult feeding, mental retardation, hypogonadism and obesity. Mitochondria play a critical role in metabolism, energy production and cell death. There are now a...

Behavioral treatment of obsessive-compulsive symptoms

Funded Year: 2009

Obsessive-compulsive (OC) symptoms are often present among youth with Prader-Willi Syndrome (PWS). They are also associated with considerable problems in the daily functioning of the child and his/her family. Although medication and behavioral treatments exist that target OC symptoms among youth without PWS, these treatments have not been...

An improved mouse model of Prader-Willi syndrome

Funded Year: 2009

Mammals have two copies of most genes, one copy having been inherited from each parent. While most genes are expressed equally from both parental copies, some genes are expressed from only one parent's copy. Genes involved in Prader-Willi syndrome are normally expressed exclusively from the chromosome inherited from the father, and PWS patients...

The autonomic nervous system in necdin-null mice

Funded Year: 2009

Background. The autonomic nervous system (ANS) performs functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection, and together with the ANS of the brain, emotion and other complex behaviors. The cells (neurons) of the ANS communicate with important organs such as...

Activation of the maternal allele at the PWS/AS domain (Year 2)

Funded Year: 2009

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....

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