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

• 批准号: 9806402
• 负责人: Cole John Ferguson
• 金额: $ 16.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806402
• 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

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 该提案描述了首席调查员科尔·J·弗格森的五年职业发展计划， 医学博士，目标是为他作为学术内科医生的独立研究生涯做好准备- 科学家。弗格森博士参加了《病理学与科学》的医师-科学家培训计划。 在华盛顿大学完成医学博士课程后，在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资格后，弗格森博士开始在 阿扎德·邦尼的实验室，在那里他研究了遗传性的泛素-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 这种不同类型的疾病的分子和细胞发病机制。对于这项提议，他有 对一只突变小鼠进行基因工程，研究一种新的遗传性神经发育障碍，这种疾病由 一个主要的E3泛素连接酶复合体突变。在研究突变小鼠的大脑发育时，他 揭示了从祖细胞分裂到表观遗传调控的主要机制 功能神经元。目标1将描述作为异常染色质基础的分子级联 成熟，而目标2将探索发育阶段与成熟阶段对基因表达的影响 大脑。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。该项目具有显著扩张的潜力，是一个 为弗格森博士独立实验室的启动奠定了坚实的科学基础。 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 邦妮是神经科学系主任，也是一位杰出的分子神经学家，她开创了 不间断电源在脑发育中的研究。Bonni博士在独立培训方面有出色的记录 调查人员在他的实验室里。此外，神经科学系还扩展了它的传统 跨分子和系统神经科学的协作和尖端实验。这 建议将广泛利用医学院在显微镜方面的世界级核心设施，并下一步- 世代排序。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 这一提议的各个方面，包括神经发育障碍、表观遗传调节和泛素信号 在大脑发育方面。病理医生-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，这个项目在将实习生转变为 通过K08机制进行独立调查。简而言之，这项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，同时提供了宝贵的技术 培训和职业发展给一位非常有前途的内科科学家。