CAREER: Unravel the Effect of Cerebral Folding on Human Brain Organoids Using an on-Chip System

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Neurological diseases remain among the largest causes of death and disability, but realistic brain models to test new therapies are still lacking. In this project, a novel miniaturized brain model will be developed to mimic brain folding. The model will be employed to study the interaction between viral infection and brain shape. The results of this work will lead to an improved understanding of how diseases impact brain function and structure. Further, this project aims to increase diversity and inclusion in STEM by recruiting underrepresented students to participate in the research in partnership with Utah State University’s Engineering Undergraduate Research Program and Native American Summer Mentorship Program.The overarching goal of this CAREER project is to unravel the impact of cerebral folding on brain function and disorders. The approaches used will focus on developing a novel brain organoid-on-chip platform, studying the pathophysiology of cerebral folding, and applying it to a high-throughput neuroviral infection model with the aid of machine learning. Through this platform, the project aims to identify gyrification-dependent neurophysiology, including cortical layering and neural plasticity. The contribution of gyrification reduction in the electrophysiology loss caused by ZIKV infection, and vice versa, the impact of gyrification levels on ZIKV infection and invasion in organoids will be determined. Scientifically, this project will contribute to bridging vital gaps regarding how gyrification/folding is impacted by diseases and shapes long-term brain physiology. The derived knowledge will also benefit the biomedical science community in the understanding of brain morphogenesis, neural development, neurophysiology, and virus infection. The established on-chip platform, machine-learning algorithms, and engineering principles will benefit the engineering community by providing new strategies for fabricating brain organoids and generating efficient neurological disease models. The outcome will also facilitate the translation of brain organoids into a realistic, efficient model for neurological diseases and drug screening.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.