Projects

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...

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...

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.

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...

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...

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...

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...

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...

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.

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.

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.

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

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.

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

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...

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.

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...

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...

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.

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.