CAREER:Engineering Brain-region-specific Organoids Derived from Human Stem Cells

Pi：Li，YanProposal No：1652992拟议的工作旨在从具有特定结构和功能的人类干细胞中生成迷你大脑(也称为脑器官)，以模仿人类的大脑。脑有机体将提供一个实验平台，使人们能够为患有神经疾病的人发现新的干预措施和药物治疗，如阿尔茨海默病、帕金森病，以及最近的婴儿小头畸形症。无法获得人脑组织限制了对患有神经疾病的人的新干预措施和药物治疗的发现，例如阿尔茨海默病、帕金森病，以及最近的婴儿小头畸形症。为了满足这一关键需求，这项拟议的工作试图创造出具有特定结构和功能的迷你大脑(也称为脑器官)，以模仿人类的大脑。为了实现这一目标，该项目将利用基于干细胞的组织工程方法，利用干细胞在合适的条件下自组装成类脑结构的能力。该研究为了解脑组织发育提供了新的途径，为药物的发现和筛选提供了一个实用的、具有临床意义的平台。具体地说，该项目将产生和表征来源于人类干细胞的同型和异型脑区特异性器官；研究细胞外基质组成和重塑对类脑器官形成的影响；以及通过调节Wnt信号通路沿吻轴和尾轴排列脑组织。这项研究的创新之处在于，将更多的细胞类型与诱导的多能干细胞来源的神经球体结合，并提供含有信号分子的细胞外基质，如在Wnt途径中，以模拟人脑中发生的空间调节。此外，该项目将建立一个互动学习平台，在学术界和产业界之间建立一座桥梁，同时缩小性别差距，增加少数族裔学生对工程学的参与。该项目将通过招募非洲裔美国人和女性学生参与拟议的研究和教育，鼓励他们追求更高的职业生涯。这项拟议工作的一个更广泛的目标是建立一个干细胞工程研究和教育项目，以吸引代表人数不足的学生参与整合的多学科研究和教育。教育和推广计划将通过以下方式实现教育目标：建立指导和研究项目以吸引女性和少数族裔学生；通过干细胞/有机体工程(也)和数字平台加强主动学习；以及建立学术界和产业界之间的管道，以提供下一代生物工程师。

PI: Li, YanProposal No: 1652992 The proposed work seeks to generate mini-brains (also called brain organoids) derived from human stem cells with defined structure and function that would mimic human brains. The brain organoids will provide an experimental platform that will enable discovery of novel interventions and pharmacological treatments for people with neurological disorders, such as Alzheimer's disease, Parkinson's disease, and more recently microcephaly in infants.Unavailability of access to human brain tissues limits the discovery of novel interventions and pharmacological treatments for people with neurological disorders, such as Alzheimer's disease, Parkinson's disease, and more recently microcephaly in infants. To address this critical need, the proposed work seeks to generate mini-brains (also called brain organoids) with defined structure and function that would mimic human brains. To achieve this, this project will utilize stem cell-based tissue engineering approach, leveraging the capability of stem cells to self-assemble into brain-like structure under suitable conditions. The proposed research provides a new approach for the understanding of brain tissue development, and a practical and clinically relevant platform for drug discovery and screening. Specifically, this project will generate and characterize homotypic and heterotypic brain-region-specific organoids derived from human stem cells; investigate the influence of extracellular matrix composition and remodeling on the formation of brain-like organoids; and, pattern brain tissue along rostral and caudal axis by modulating the Wnt signaling pathway. The novelty of the proposed research is that additional cell types are incorporated with induced pluripotent stem cell-derived neural spheroids and the extracellular matrices containing signaling molecules such as in Wnt pathway are provided to mimic spatial regulations that occur in human brain. In addition, the project will establish an interactive learning platform to form a bridge between academia and industry, while simultaneously reducing gender disparity and increasing the participation of minority students in engineering. The project will encourage African American and female students to pursue advanced career by recruiting them to participate in the proposed research and education. A broader goal of the proposed work is to establish a stem cell engineering research and education program that will attract underrepresented students for integrated multidisciplinary research and education. The education and outreach plan will accomplish the educational objectives by: establishing mentoring and research projects to attract female and minority students, enhancing Active Learning through Stem cell/Organoid engineering (ALSO) and digital platforms, and building an academia-industry pipeline to supply next-generation bioengineers.