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

神经系统疾病仍然是导致死亡和残疾的最大原因之一，但用于测试新疗法的真实大脑模型仍然缺乏。在这个项目中，将开发一种新的小型化大脑模型来模拟大脑折叠。该模型将用于研究病毒感染与大脑形状之间的相互作用。这项工作的结果将导致对疾病如何影响大脑功能和结构的更好理解。此外，该项目旨在通过招募代表性不足的学生参与与犹他州立大学工程本科研究计划和美国原住民夏季指导计划合作的研究，增加STEM的多样性和包容性。这个CAREER项目的总体目标是揭示大脑折叠对大脑功能和疾病的影响。所使用的方法将集中于开发一种新的脑类器官芯片平台，研究大脑折叠的病理生理学，并在机器学习的帮助下将其应用于高通量神经病毒感染模型。通过这个平台，该项目旨在确定旋转依赖的神经生理学，包括皮层分层和神经可塑性。将确定旋转减少对ZIKV感染引起的电生理损失的贡献，反之亦然，旋转水平对ZIKV感染和入侵类器官的影响。从科学上讲，该项目将有助于弥合关于疾病如何影响旋转/折叠以及如何形成长期大脑生理的重要空白。衍生的知识也将有利于生物医学科学界对脑形态发生、神经发育、神经生理学和病毒感染的理解。已建立的芯片平台、机器学习算法和工程原理将为制造脑类器官和生成有效的神经系统疾病模型提供新的策略，从而使工程界受益。这一结果也将促进脑类器官转化为神经系统疾病和药物筛选的现实、有效的模型。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.