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: 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
• 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

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.

项目总结/摘要 本提案描述了首席研究员科尔J.弗格森的五年职业发展计划， 医学博士，博士，为他准备一个独立的研究生涯作为一个学术医生的目标- 科学家Ferguson博士参加了病理学和医学科学家培训计划。 在完成医学博士/博士课程后，在华盛顿大学免疫学系， 密歇根在解剖学和神经病理学住院医师奖学金之后，Ferguson博士开始在 阿扎德·邦尼的实验室，他在那里研究遗传性疾病中的泛素-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对 这类不同疾病的分子和细胞发病机制。对于这一提议，他 通过基因工程改造一只突变小鼠，研究一种新的遗传性神经发育障碍， 在主要的E3泛素连接酶复合物中的突变。在研究突变小鼠的大脑发育时， 揭示了在从分裂的祖细胞到 功能性神经元目的1将描述异常染色质的分子级联反应 成熟，而目标2将探讨基因表达的后果，在发展与成熟 个脑袋在这个项目的过程中，弗格森博士将成为影像学、生物化学和基因组学方面的专家 研究大脑表观遗传学的方法。该项目具有重大扩展的潜力，是一个 为弗格森博士的独立实验室的开始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 Bonni是神经科学系主任，也是一位杰出的分子神经科学家， UPS在大脑发育中的研究。Bonni博士在独立培训方面有着出色的记录 实验室里的研究人员。此外，神经科学系还扩大了其传统， 跨分子和系统神经科学的合作和尖端实验。这 该提案将广泛利用医学院在显微镜和下一个世界级的核心设施- 世代排序弗格森博士受人尊敬的科学顾问团的专业知识涵盖了所有 这一建议的各个方面，包括神经发育障碍，表观遗传调控和泛素信号转导 在大脑发育中。病理学医生-科学家培训计划委员会将在以下方面发挥积极作用： 博士弗格森的职业发展，这个计划有一个过渡到学员的出色记录， 通过K 08机制进行独立调查。简而言之，这项建议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，以一个非常有前途的医生，科学家。