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

摘要/项目总结 此应用程序提出了一个为期五年的指导研究和培训计划，将准备博士凯瑟琳 卡德韦尔将成为皮层发育和电路组装领域的领导者。卡德维尔博士完成了她的医学博士学位 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 在Andreas Tolias博士的实验室中塑造皮层回路的血统，现在正在完成她的临床研究 在加州大学旧金山弗朗西斯科的神经病理学。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的病理过程的理解 紊乱该项目将促进她的独立研究计划的基础发现，因为她 试图描述皮质区域特化的机制和功能后果。 人类大脑的不同区域产生了独特的认知能力。例如， 人类的外侧前额叶皮层（PFC）被认为是高级认知过程的基础， 决策、计划和工作记忆。最近的数据表明，维甲酸（RA），一种衍生物， 维生素A，作为人类PFC早期发展的关键参与者;然而， 哪个RA指定PFC身份是未知的。这项提案利用了人类诱导多能干细胞- 衍生的脑类器官模型，它概括了早期人类大脑发育的许多方面，以测试 假设RA以细胞类型特异性方式起作用以指定PFC身份。使用这个模型，博士。 Cadwell提出：1）确定核受体和基因调控元件，介导RA信号 在人皮质祖细胞中，以及2）确定类PFC区域命运在RA诱导后是否稳定。这 这项工作将产生关于RA在大脑皮层模式中的作用的基本知识， 提供与异常皮质区域特化相关的神经发育障碍的见解。 拟议的职业发展计划包括大脑类器官模型，表观遗传 大规模数据集的技术和分析。卡德韦尔博士将学习所有的技能， 独立的研究生涯，包括监督学员和工作人员，赠款写作，和科学 通信她组建了一个世界级的导师团队， 类器官和人脑发育（主要导师，Tomasz Nowakowski博士），分子机制 皮质发育和模式（共同导师博士约翰鲁宾斯坦和咨询委员会成员博士。 Sam Pleasure）、基因调控（咨询委员会成员Nadav Ahituv博士）、大规模基因组学分析、 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）。博士 卡德韦尔，她的导师，在加州大学旧金山分校病理学系完全致力于这一建议，并 她的目标是在完成这一培训期间成为一名独立的神经科学家。

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.