Projects Archive - Foundation for Prader-Willi Research | Neurobiology

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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Consequences of targeted SNORD116 deletion in human and mouse neurons

Funded Year: 2018

Abstract 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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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. false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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 false

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