Projects

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

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 false

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

Prader-Willi Syndrome (PWS) is a condition characterized by growth hormone deficiency, hypogonadism, various behavioral disturbances, an insatiable hunger drive 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 therapies for false

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

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 false

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

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 false

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

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 false

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

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 false

Hypocretin/orexin deficiency in Prader-Willi syndrome animal models

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

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

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

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 false

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

(Year 2 of this project)

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

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

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

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

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

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

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

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 false

Role of PWCR1 snoRNAs in Prader-Willi Syndrome

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 false

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

An insatiable appetite, 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 behavioral false

PWS mouse model with deleted snoRNA cluster

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 false

Exploring the potential of using demethylation drugs to treat PWS

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 false

Evaluation of sensory processing in individuals with PWS

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. false

Endocrine and molecular basis for Prader-Willi syndrome

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 false

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

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 false

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

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. false

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

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 false

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

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, false

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

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 false

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

An insatiable appetite, 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 exacerbation of false

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

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 false

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

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 false

Behavioral treatment of obsessive-compulsive symptoms

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 false

An improved mouse model of Prader-Willi syndrome

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 false

The autonomic nervous system in necdin-null mice

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

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

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. false

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