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：
10251284
负责人：
Cole John Ferguson
金额：
$ 16.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251284
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.

项目摘要/摘要该建议描述了首席研究员科尔·J·弗格森（Cole J. Ferguson）的五年职业发展计划医学博士，博士，目的是为他做好准备从事学术医师的独立研究职业 - 科学家。弗格森博士在病理学和华盛顿大学免疫学系完成了大学的MD/博士学位课程后密歇根州。遵循解剖学和神经病理学的居住 - 居民，弗格森博士开始工作阿扎德·邦尼（Azad Bonni）的实验室，他在那里研究泛素蛋白蛋白酶体系统（UPS）神经发育障碍。弗格森博士的研究的长期目标是提高理解这种多种疾病类别的分子和细胞发病机理。对于这个建议，他有基因设计的突变小鼠研究了由主要E3泛素连接酶复合物中的突变。在调查突变小鼠的大脑发育时，他在从分裂祖细胞到的过渡期间发现了表观遗传调节的主要机制功能性神经元。 AIM 1将表征基于异常染色质的分子级联成熟，而AIM 2将探索发展与成熟的基因表达的后果脑。在这个项目的过程中，弗格森博士将成为成像，生化和基因组学专家研究大脑表观遗传学的方法。该项目具有重大扩展的潜力，是弗格森博士独立实验室开始的杰出科学基础。华盛顿大学是弗格森博士实现这些目标的理想环境。他的导师阿扎德博士 Bonni是神经科学系主任，也是杰出的分子神经科学家对大脑发育中UPS的研究。 Bonni博士拥有独立培训的出色记录他的实验室的调查人员。此外，神经科学系已扩大了其传统分子和系统神经科学的协作和尖端实验。这提案将在显微镜和接下来的医学院世界一流的核心设施中广泛使用生成测序。弗格森博士尊敬的科学咨询小组的专业知识包括所有该建议的各个方面，包括神经发育障碍，表观遗传调节和泛素信号传导在大脑发展中。病理医师科学家培训计划委员会将在弗格森博士的职业发展，该计划在过渡到学员到独立研究人员通过K08机制。简而言之，该提议将在几个发育神经生物学中表观遗传调节的重要方面，同时提供了宝贵的技术培训和职业发展为一位非常有前途的医师科学家。