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 changes in gene expression in mice lacking MAGEL2 contribute to the hyperphagia and obesity in PWS. Once the causal role of candidate cells and genes has been confirmed, we will identify drug targets that would be expected to inhibit cells that drive appetite or activate cells that reduce appetite. These studies will lay a solid foundation of our understanding of the mechanisms underlying hyperphagia and obesity in PWS, and more importantly, provide a rational (i.e; non-empiric) means for identifying drugs that engage those drug targets to treat the disorder.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
The purpose of the proposed project is to investigate the pathophysiological role of SNORD116, a gene located in the genetic region that causes PWS. This gene’s mechanism of action remains unknown, but it has the potential to affect the activity of other genes in a way that could account for the complex clinical features of PWS. We hypothesize that SNORD116 interacts with other genes that mediate PWS-related clinical characteristics. We will test this proposition by testing the effects of Snord116 on a gene, DGKK, which we have implicated in PWS in studies of mouse and human brain. DGKK participates in chemical processes in the brain that are relevant to PWS. If SNORD116 is confirmed to interact with DGKK in brain regions relevant to PWS and influences DGKK expression levels, we will have identified a basic molecular mechanism that could account for some of the protean clinical manifestations of PWS. Implication of SNORD116 would rationalize efforts to activate the silent maternal copy of the gene; and implication of “downstream” genes like DGKK would suggest pharmacological targets for mitigation.
Yiying Zhang, Ph.D.
Yiying Zhang, Ph.D.