The role of retinoic acid signaling in patterning the human cerebral cortex

摘要/项目摘要 本申请提供了一份为期五年的有指导的研究和培训计划，该计划将为凯瑟琳博士做好准备 卡德韦尔将成为皮质开发和电路组装领域的领先者。卡德韦尔博士完成了医学博士学位 贝勒医学院神经科学博士，在那里她研究了细胞类型和细胞的作用 在安德烈亚斯·托利亚斯博士的实验室中塑造皮质回路的血统，现在正在完成她的临床研究员资格 加州大学旧金山分校的神经病理学专业。卡德韦尔博士的长期职业目标是 促进我们对神经发育和神经精神病学基础的病理过程的理解 精神错乱。该项目将促进她的独立研究计划的基础性发现，因为她 旨在描述皮质区域规范的机制和功能后果。 人类大脑的不同区域会产生独特的认知能力。例如，扩展 人类的外侧前额叶皮质(PFC)被认为是高级认知过程的基础，如 决策、计划和工作记忆。最近的数据表明，维甲酸(RA)是维甲酸的衍生物 维生素A，作为人类PFC早期发展的关键因素；然而，通过 哪个RA指定PFC身份是未知的。这一提议利用了人类诱导的多能干细胞- 衍生的大脑器官模型，它概括了人类早期大脑发育的许多方面，以进行测试 RA以特定细胞类型的方式起作用以确定PFC身份的假说。使用这个模型，Dr。 卡德韦尔建议1)确定介导RA信号转导的核受体和基因调控元件 2)确定类风湿因子在类风湿关节炎诱导后是否稳定。这 这项工作将产生关于类风湿因子在大脑皮层模式形成中的作用的基础知识，并可能 提供对神经发育障碍相关的皮质区域异常规格的洞察。 拟议的职业发展计划包括培训大脑器官模型、表观遗传学 大规模数据集的技术和分析。卡德韦尔博士将学习一项 独立研究生涯，包括指导受训者和工作人员，撰写拨款，以及科学研究 沟通。她组建了一支世界级的导师团队，在 有机化合物与人脑发育(初级导师托马斯·诺瓦科夫斯基博士)，分子机制 (共同导师约翰·鲁宾斯坦博士和咨询委员会成员Dr。 SAM愉悦)，基因调控(咨询委员会成员纳达夫·阿赫图夫博士)，大规模分析 基因组数据(Katie Pollard博士)和神经发育障碍的神经病理学(Eric Huang博士)。Dr。 卡德韦尔、她的导师和加州大学旧金山分校的病理学系完全致力于这项提议，并 她的目标是在完成这段培训后成为一名独立的医生-神经学家。

ABSTRACT/PROJECT SUMMARY This application presents a five-year mentored research and training plan that will prepare Dr. Cathryn Cadwell to be a leader in the field of cortical development and circuit assembly. Dr. Cadwell completed her MD and PhD in Neuroscience at Baylor College of Medicine, where she studied the role of cell type and cell lineage in shaping cortical circuits in the lab of Dr. Andreas Tolias, and is now completing her clinical fellowship in Neuropathology at the University of California, San Francisco. Dr. Cadwell’s long-term career goal is to advance our understanding of the pathological processes underlying neurodevelopmental and neuropsychiatric disorders. This project will facilitate foundational discoveries for her independent research program, as she seeks to delineate the mechanisms and functional consequences of cortical areal specification. Different areas of the human brain give rise to unique cognitive abilities. For example, expansion of the lateral prefrontal cortex (PFC) in humans is thought to underlie higher-order cognitive processes such as decision-making, planning and working memory. Recent data has implicated retinoic acid (RA), a derivative of vitamin A, as a key player in the early development of the PFC in humans; however, the precise mechanism by which RA specifies PFC identities is unknown. This proposal leverages a human induced pluripotent stem cell– derived cerebral organoid model, which recapitulates many aspects of early human brain development, to test the hypothesis that RA acts in a cell type–specific manner to specify PFC identities. Using this model, Dr. Cadwell proposes to 1) identify the nuclear receptors and gene regulatory elements that mediate RA signaling in human cortical progenitors and 2) determine whether PFC-like areal fate is stable after RA induction. This work will generate fundamental knowledge about the role of RA in patterning the cerebral cortex, and may provide insights into neurodevelopmental disorders associated abnormal cortical areal specification. The proposed career development plan includes training in cerebral organoid models, epigenetic techniques and analysis of large-scale data sets. Dr. Cadwell will learn all of the skills needed for an independent research career, including supervising trainees and staff, grant writing, and scientific communication. She has assembled a world-class mentorship team with complementary expertise in organoids and human brain development (Primary mentor, Dr. Tomasz Nowakowski), molecular mechanisms of cortical development and patterning (Co-mentor Dr. John Rubenstein and Advisory Committee Member Dr. Sam Pleasure), gene regulation (Advisory Committee Member Dr. Nadav Ahituv), analysis of large-scale genomic data (Dr. Katie Pollard), and neuropathology of neurodevelopmental disorders (Dr. Eric Huang). Dr. Cadwell, her mentors, and the Department of Pathology at UCSF are fully committed to this proposal and to her goal of becoming an independent physician-neuroscientist by the completion of this training period.