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 hypothalamic neurons. Characterization of these new cellular models for PWS may lead to the identification of new therapeutic targets.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing all 7 research projects funded in this grant cycle here.
Prader-Willi syndrome (PWS) is caused by a deletion of a small region on chromosome 15 (15q11-q13) that was inherited from the father. The unique genetic nature of PWS has been known for many years, but the precise way it causes the developmental abnormalities is not understood, in part because the deleted region contains many different genes. To investigate this, we capitalized on new techniques for growing human stem cells and manipulating their chromosomes. Using CRISPR genome editing technique, we generated stem cells with PWS deletions including deletions of the full region as well as deletions of the individual genes separately. Moving forward, we will differentiate all these PWS stem cells into neurons from the hypothalamus, a brain region thought to be critically important for obesity and behavioral abnormalities in PWS patients. We will then study the cellular properties of these PWS neurons by comparing them to neurons without the deletions. This will help us determine whether a given single gene is responsible for causing PWS abnormalities. The cell lines generated will establish a powerful resource for the research community. Ultimately, the results will provide a new, genetically precise, human cellular model system for investigators in the field, insights into how PWS deletions translate into abnormal development, and a key foundation for figuring out which genes are responsible for PWS. Hopefully, the generation of this resource and the insights it will provide will lead to new therapeutic targets for PWS, which can then be validated using our cellular system to determine whether they ameliorate PWS-associated cellular abnormalities.
Derek Tai, Ph.D
Massachusetts General Hospital
Derek Tai, Ph.D