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

视黄酸信号在人类大脑皮层模式化中的作用

• 批准号: 10590628
• 负责人: Cathryn Rene Cadwell
• 金额: $ 23.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590628
• 关键词: Advisory Committees; Anatomy; Animal Model; Animals; Anterior; Area; Automobile Driving; Axon; Binding; Biological Assay; Brain; California; Cell Lineage; Cells; Cerebral cortex; Cerebrum; Clinical; Committee Members; Communication; DNA Binding; Data; Decision Making; Development; Development Plans; Doctor of Philosophy; Enhancers; Environment; Epigenetic Process; Evolution; Experimental Models; Exposure to; FGF8 gene; Family; Fellowship; Fibroblast Growth Factor; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Predisposition to Disease; Geniculate body structure; Goals; Grant; Human; Immunohistochemistry; In Vitro; Knowledge; Laboratories; Lateral; Learning; Location; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular; Motor; Mus; Neurodevelopmental Disorder; Neuroglia; Neurons; Neurosciences; Nuclear; Nuclear Receptors; Organoids; Pathologic Processes; Pathology; Patients; Pattern; Phenotype; Physicians; Play; Prefrontal Cortex; Preventive; Primates; Process; Prosencephalon; Publishing; RARB gene; RARG gene; Radial; Regulator Genes; Regulatory Element; Reporter; Research; Resolution; Retinoic Acid Binding; Retinoic Acid Receptor; Role; San Francisco; Schizophrenia; Shapes; Short-Term Memory; Signal Pathway; Signal Transduction; Specific qualifier value; Techniques; Testing; Thalamic structure; Therapeutic; Tissues; Training; Transplantation; Tretinoin; Universities; Untranslated RNA; Vitamin A; Work; Writing; Xenograft procedure; area striata; autism spectrum disorder; career; career development; cell type; cognitive ability; cognitive process; college; comparative; excitatory neuron; experimental study; genome sequencing; genome-wide; genomic data; induced pluripotent stem cell; insight; large scale data; member; molecular phenotype; morphogens; neonatal mice; nerve stem cell; nervous system disorder; neural; neuropathology; neuropsychiatric disorder; organoid transplantation; pharmacologic; pleasure; postmitotic; prenatal; progenitor; programs; protein expression; receptor binding; response; skills; transcription factor; whole genome

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.

摘要/项目摘要 该申请提出了一个为期五年的指导研究和培训计划，将为 Cathryn 博士做好准备 Cadwell 致力于成为皮质开发和电路组装领域的领导者。卡德威尔博士完成了医学博士学位 贝勒医学院神经科学博士和博士，研究细胞类型和细胞的作用 在 Andreas Tolias 博士的实验室中塑造皮质回路的谱系，目前正在完成她的临床研究 旧金山加利福尼亚大学神经病理学博士。卡德威尔博士的长期职业目标是 增进我们对神经发育和神经精神病理过程的理解 失调。该项目将促进她的独立研究计划的基础发现，因为她 旨在描述皮质区域规范的机制和功能后果。 人脑的不同区域产生独特的认知能力。例如，扩展 人类的外侧前额皮质（PFC）被认为是高阶认知过程的基础，例如 决策、计划和工作记忆。最近的数据表明视黄酸 (RA) 是一种衍生物 维生素 A，作为人类 PFC 早期发育的关键参与者；然而，精确的机制是 哪个 RA 指定 PFC 身份尚不清楚。该提案利用了人类诱导多能干细胞—— 衍生的大脑类器官模型，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发挥作用来指定 PFC 身份。使用这个模型，博士。 Cadwell 建议 1) 鉴定介导 RA 信号传导的核受体和基因调控元件 2) 确定人类皮质祖细胞中 PFC 样区域命运在 RA 诱导后是否稳定。这 这项工作将产生关于 RA 在大脑皮层模式化中的作用的基础知识，并且可能 提供对与异常皮质区域规范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、表观遗传学的培训 大规模数据集的技术和分析。卡德威尔博士将学习成为一名医生所需的所有技能 独立研究生涯，包括监督受训者和工作人员、资助写作和科学 沟通。她组建了一支世界一流的导师团队，在以下领域具有互补的专业知识 类器官和人类大脑发育（主要导师，Tomasz Nowakowski 博士），分子机制 皮质发育和模式化的研究（联合导师约翰·鲁宾斯坦博士和顾问委员会成员约翰·鲁宾斯坦博士） Sam Pleasure），基因调控（顾问委员会成员 Nadav Ahituv 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）。博士。 卡德韦尔、她的导师以及加州大学旧金山分校病理学系完全致力于这项提案并 她的目标是在完成本培训期后成为一名独立的医生兼神经科学家。