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

基本信息

批准号：
10426684
负责人：
Cathryn Rene Cadwell
金额：
$ 21.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10426684
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 Lead Learning Location Mediating Medicine Mentors Mentorship Modeling Molecular Motor Mus Neurodevelopmental Disorder Neuroglia Neurons Neurosciences Nuclear Nuclear Receptor Gene Nuclear Receptors Organoids Pathologic Processes Pathology Patients Pattern Pharmacology Phenotype Physicians Play Prefrontal Cortex Preventive Primates Process Prosencephalon Publishing RARB gene RARG gene Radial Regulator Genes Regulatory Element Reporter Research Research Training Resolution Retinoic Acid Binding Retinoic Acid Receptor Role San Francisco Schizophrenia Shapes Short-Term Memory Signal Pathway Signal Transduction Specific qualifier value Supervision Techniques Testing Thalamic structure Therapeutic Tissues To specify Training Transplantation Tretinoin Universities Untranslated RNA Vitamin A Work Writing Xenograft procedure area striata autism spectrum disorder base 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 neuropathology neuropsychiatric disorder organoid transplantation pleasure prenatal progenitor programs protein expression receptor binding relating to nervous system response skills transcription factor whole genome

项目摘要

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 博士完成了医学博士学位，成为皮质发育和电路组装领域的领导者。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卡德威尔博士在旧金山加利福尼亚大学获得神经病理学博士学位。我们对神经发育和神经精神病理过程的理解该项目将促进她的独立研究项目的基础发现，因为她旨在描述皮质区域规范的机制和功能后果。人脑的不同区域会产生独特的认知能力，例如，大脑的扩展。人类的外侧前额皮质（PFC）被认为是高阶认知过程的基础，例如最近的数据表明，视黄酸 (RA) 是一种维生素 A 的衍生物。维生素 A 作为人类 PFC 早期发育的关键参与者，但其确切机制尚不清楚； RA 指定的 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 RA 以特定细胞类型的方式发挥作用来指定 PFC 身份的假设，Dr. 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 RA 诱导后 PFC 样区域命运是否稳定。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、表观遗传学等方面的培训卡德威尔博士将学习大规模数据集的技术和分析。独立研究生涯，包括监督受训者和工作人员、资助写作和科学她组建了一支世界一流的导师团队，在各方面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 John Rubenstein 博士和顾问委员会成员 Dr. John Rubenstein） 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）。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。