Ubiquitin signaling in epigenetic regulation of neuronal development

神经元发育表观遗传调控中的泛素信号传导

基本信息

批准号：
10015330
负责人：
Cole John Ferguson
金额：
$ 1.16万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2020-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015330
关键词：
Affect Amish Anatomy Architecture Behavioral Behavioral Assay Binding Biochemical Brain Brain Diseases Cell Cycle Cell Cycle Progression ChIP-seq Charge Chromatin Clinical Investigator Award Collaborations Complex Core Facility Cullin Proteins Data Development Development Plans Developmental Delay Disorders Developmental Process Disease Doctor of Philosophy Enrollment Epigenetic Process Exhibits Fellowship Follow-Up Studies Foundations Gene Expression Gene Expression Regulation Genes Genetic Genetic Engineering Genetic Transcription Genome Genomic approach Goals Hereditary Disease Heterochromatin Histones Holoenzymes Image Immunology Informatics Inherited Investigation K-Series Research Career Programs Knock-out Laboratories Lead Lysine Massive Parallel Sequencing Mendelian disorder Mentors Methods Michigan Microscopy Mitosis Mitotic Mitotic Chromosome Molecular Morphogenesis Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neuronal Differentiation Neurons Neurosciences Nuclear Pathogenesis Pathology Pathway interactions Patients Phenotype Physicians Play Principal Investigator Process Protein phosphatase RNA Interference Research Research Personnel Residencies Role Scientist Serine Signal Pathway Signal Transduction Structure System Testing Training Training Programs Transcript Ubiquitin Ubiquitination Universities Washington anaphase-promoting complex career career development chromatin immunoprecipitation cohort developmental neurobiology differential expression disease-causing mutation epigenetic regulation experience experimental study heterochromatin-specific nonhistone chromosomal protein HP-1 improved in vivo insight knock-down medical schools mind control multicatalytic endopeptidase complex mutant mutant mouse model neurodevelopment neuron development neuropathology next generation sequencing novel null mutation overexpression prevent proband progenitor programs quantitative imaging surfactant synaptogenesis transcriptome sequencing ubiquitin-protein ligase

项目摘要

Project Summary/Abstract This proposal describes the five-year career development plan for Principal Investigator Cole J. Ferguson, MD, PhD, with the goal of preparing him for an independent research career as an academic physician- scientist. Dr. Ferguson enrolled in the Physician-Scientist Training Program within the Pathology & Immunology Department at Washington University after completing the MD/PhD program at the University of Michigan. Following the Anatomic and Neuropathology residency-fellowship, Dr. Ferguson began working in the laboratory of Azad Bonni, where he studies the ubiquitin-proteasome system (UPS) in inherited neurodevelopmental disorders. The long-term goal of Dr. Ferguson's research is to improve the understanding of the molecular and cellular pathogenesis of this diverse class of disorders. For this proposal, he has genetically engineered a mutant mouse to study a novel inherited neurodevelopmental disorder caused by mutation in a major E3 ubiquitin ligase complex. While investigating brain development in mutant mice, he uncovered a major mechanism of epigenetic regulation during the transition from dividing progenitors to functional neurons. Aim 1 will characterize the molecular cascade that underlies aberrant chromatin maturation, while Aim 2 will explore the consequences on gene expression in the developing versus mature brain. In the course of this project, Dr. Ferguson will become an expert in imaging, biochemical and genomics approaches to study epigenetics in the brain. This project has the potential for significant expansion and is an outstanding scientific foundation for the start of Dr. Ferguson's independent laboratory. Washington University is the ideal setting for Dr. Ferguson to achieve these aims. His mentor Dr. Azad Bonni is Chair of the Neuroscience Department and a preeminent molecular neuroscientist who has pioneered the study of the UPS in brain development. Dr. Bonni has an outstanding record of training independent investigators in his laboratory. In addition, the Department of Neuroscience has expanded upon its tradition of collaboration and cutting-edge experimentation across both molecular and systems neuroscience. This proposal will make extensive use of the School of Medicine's world-class core facilities in microscopy and next- generation sequencing. The expertise of Dr. Ferguson's esteemed scientific advisory panel encompasses all aspects of this proposal, including neurodevelopmental disorders, epigenetic regulation, and ubiquitin signaling in brain development. The Pathology Physician-Scientist Training Program committee will play an active role in Dr. Ferguson's career development, and this program has an outstanding record of transitioning trainees into independent investigators through the K08 mechanism. In short, this proposal will make progress on several important aspects of epigenetic regulation in developmental neurobiology, while providing invaluable technical training and career development to a highly promising physician-scientist.

项目概要/摘要该提案描述了首席研究员 Cole J. Ferguson 的五年职业发展计划，医学博士、博士，目标是为他作为一名学术医生的独立研究生涯做好准备- 科学家。弗格森博士参加了病理学和医学领域内的医师科学家培训计划在华盛顿大学完成医学博士/博士课程后，进入华盛顿大学免疫学系密歇根州。在获得解剖学和神经病理学住院医师培训后，弗格森博士开始在 Azad Bonni 的实验室，他在那里研究遗传性中的泛素蛋白酶体系统 (UPS) 神经发育障碍。弗格森博士研究的长期目标是提高人们对此类不同疾病的分子和细胞发病机制。对于这个提议，他对突变小鼠进行基因改造，以研究由以下原因引起的新型遗传性神经发育障碍主要 E3 泛素连接酶复合体发生突变。在研究突变小鼠的大脑发育时，他揭示了从分裂祖细胞向分裂祖细胞转变过程中表观遗传调控的主要机制功能神经元。目标 1 将表征异常染色质背后的分子级联成熟，而目标 2 将探讨发育与成熟中基因表达的影响脑。在这个项目的过程中，弗格森博士将成为成像、生化和基因组学方面的专家研究大脑表观遗传学的方法。该项目具有显着扩张的潜力，是一个为弗格森博士独立实验室的启动奠定了杰出的科学基础。华盛顿大学是弗格森博士实现这些目标的理想场所。他的导师阿扎德博士邦尼是神经科学系主任，也是一位杰出的分子神经科学家，他开创了大脑发育中 UPS 的研究。 Bonni 博士拥有独立培训的杰出记录调查员在他的实验室里。此外，神经科学系还扩展了其传统分子和系统神经科学领域的合作和前沿实验。这该提案将广泛利用医学院在显微镜和下一代方面的世界一流核心设施世代测序。弗格森博士受人尊敬的科学顾问小组的专业知识涵盖了所有领域该提案的各个方面，包括神经发育障碍、表观遗传调控和泛素信号传导在大脑发育中。病理医师-科学家培训计划委员会将在以下方面发挥积极作用：弗格森博士的职业发展，以及该计划在将学员转变为通过 K08 机制进行独立调查。简而言之，该提案将在几个方面取得进展发育神经生物学中表观遗传调控的重要方面，同时提供宝贵的技术为非常有前途的医师科学家提供培训和职业发展。