Unraveling the mechanism of PWS by molecular dissection of driver genes in hypothalamic neuron model (Year 2)

Funding Summary

Dr. Derek Tai developed PWS cell lines representing type 1 and 2 deletions and has grown them as 3-D brain organoids, recapitulating the hypothalamus, in a dish. He has applied cutting edge technology to understand how PWS neurons differ from typical neurons and has generated data on gene expression changes. In year 2, he will expand the study to include assessment of energy/metabolism and electrophysiology to understand the underlying mechanism of disease in PWS.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

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 canonical deletions of the full region. Moving forward, we will differentiate all these PWS stem cells into three-dimensional (3D) organoid model from the hypothalamus, a brain region thought to be critically important for obesity and behavioral abnormalities in PWS patients. We will then study the level of expression of all genes and the cellular properties of these PWS organoids by comparing them to organoids without the deletions. This will help us determine whether given signaling pathways and aberrant cell geometry are responsible for causing PWS abnormalities. The cell models 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 molecular and cellular abnormalities.

Funded Year:

2022

Awarded to:

Derek Tai, Ph.D.

Amount:

$108,000

Institution:

Massachusetts General Hospital

Researcher:

Derek Tai, PhD

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