Disentangling developmental and hormone responsive dysfunction of human hypothalamic circuits in Prader-Willi Syndrome

Funding Summary

The focus of our proposal is to unravel the complexities of developmental and hormone-responsive dysfunction within human hypothalamic circuits in Prader-Willi Syndrome using cutting edge human brain circuits within a petri dish using organoids.

Lay Abstract

The focus of our proposal is to unravel the complexities of developmental and hormone-responsive dysfunction within human hypothalamic circuits in Prader-Willi Syndrome.
Currently, the absence of animal models that accurately replicate the human characteristics of PWS can be attributed to the intricate genetic components of PWS. Traditional studies on human brain cells have been limited to post-mortem analyses, posing significant challenges in comprehending the disease's impact on the brain. The constraints of studying deceased tissues restrict our ability to fully discern how various biological system components contribute to the disease, as live tissue specimens are essential for such investigations. Unfortunately, extracting cell samples from living brains for study is impractical. Human organoid technology is a transformative tool that can propel genetic disease research forward,
providing an applicable model for the exploration of human biology. By fully understanding the precise biological basis in the brain for overeating in PWS patients, a roadmap for focused research to treat this condition will be created.
Over the past decade, three distinguished research laboratories at Emory have collaborated extensively to develop tools capable of generating, modeling, and constructing human brain circuits within a petri dish using organoids. Leveraging skin small samples from patients, these innovative methods aim to push the boundaries of modeling human brain disorders. Prader-Willi Syndrome presents an excellent and pivotal opportunity to apply these recently developed tools to a specific disorder. The urgent need to comprehend the exact cause of insatiable hunger in PWS patients, coupled with the absence of available therapeutics, underscores the significance of our research. Understanding these mechanisms will create a path to
effective future therapeutics.
Our research seeks to address the fundamental question: Is disrupted hypothalamic function the primary cause of obesity, followed by subsequent endocrine alterations, or is defective endocrine regulation the leading cause of hypothalamic dysfunction? Our approach integrates state-of-the-art neuroscience technology with human brain organoids to tackle this critical and unanswered question. With the invaluable support of the Foundation for Prader-Willi Research, we are enthusiastic about embarking on this endeavor and utilizing these cutting-edge technologies to expedite the development of new treatments for the PWS community.