Elucidating the Spatiotemporal Regulation of a Long Non-Coding RNA Required for Neurodevelopment

阐明神经发育所需的长非编码 RNA 的时空调节

• 批准号: 10331054
• 负责人: Sandeep Nagaraj Wontakal
• 金额: $ 19.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2022-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331054
• 关键词: Address; Alleles; Binding; Binding Sites; Bioinformatics; Biological; Biological Sciences; Caenorhabditis elegans; Cells; Cellular biology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; Complement; Complex; Coupled; Development; Development Plans; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Electrophoretic Mobility Shift Assay; Elements; Environment; Foundations; Genes; Genetic; Genetic Screening; Genetic Transcription; Genome; Genomic medicine; Genomics; Goals; Health; Human; In Vitro; Inherited; Institutes; Lead; Leadership; Logic; Mediating; Mentors; Mentorship; Microscopy; Molecular; Mutate; Mutation; Nervous system structure; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences; Pathogenicity; Pathologist; Pathology; Pathway interactions; Patients; Pattern; Physicians; Process; Proteins; RNA; Rare Diseases; Recording of previous events; Regulation; Regulatory Element; Repression; Research; Research Personnel; Scientist; Sexual Maturation; Solid; System; Testing; Training; Transcription Coactivator; Universities; Untranslated RNA; Up-Regulation; Variant; Work; base; blocking factor; career; career development; chromatin immunoprecipitation; design; experience; experimental study; functional genomics; genetic analysis; genetic approach; genome sequencing; in vivo; in vivo evaluation; insight; interest; male; nervous system development; neurodevelopment; neurogenetics; novel; professor; programs; skills; spatiotemporal; tool; transcription factor; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT This proposal outlines a comprehensive five-year mentored career development plan with the goal of preparing the candidate, Sandeep Wontakal, M.D., Ph.D., for an independent academic research career as a physician- scientist. The training plan is designed to acquire and refine skills in three critical aspects essential for a successful career as a physician-scientist: 1) establishing the basis for an independent research program 2) expanding clinical expertise and 3) enhancing mentorship/leadership skills. His strong background in functional genomics from his graduate work and his experience as a board-certified molecular pathologist with expertise in genomic testing of rare disorders, provides a solid foundation upon which the training plan builds. Dr. Wontakal’s long-term research and clinical interest is to decode the information transmitted in the non-coding genome and how mutations in these regions can lead to neurodevelopmental disorders. The scientific aspects of the proposal will be mentored by Dr. Oliver Hobert, Professor and HHMI Investigator, who is a leading neuroscientist with a long track record of mentoring successful trainees. Dr. Wontakal will develop further clinical acumen in identifying pathogenic non-coding mutations under the guidance of the preeminent human geneticist, Dr. David Goldstein, Director of the Institute for Genomic Medicine at Columbia University. An advisory panel of renowned physician- scientists and an expert in RNA neurobiology will also oversee the candidate’s progress and provide guidance. This work will be performed at Columbia University under the auspices of the Department of Biological Sciences, one of the birthplaces of genetics, and the Department of Pathology & Cell Biology, which has a long history of training physician-scientists. The vibrant scientific and clinical environment at Columbia with its world-renowned neuroscience community, will serve as an ideal environment to successfully execute the proposed training plan. Taking advantage of the powerful genetic and cell biological tools available in C. elegans, Dr. Wontakal will study how the long non-coding RNA (lncRNA), lep-5, functions in regulating the timing of neurodevelopment. Lep-5 expression is temporally regulated and preliminary results show lep-5 is required for proper sexual maturation of the male nervous system. Dr. Wontakal has generated several novel strains to determine how the precise spatiotemporal expression of lep-5 is established through studying the following three aims: 1) determine the cis regulatory elements controlling lep-5 expression 2) determine how the transcription factor lin-14 represses lep- 5 expression 3) determine the transcriptional activator(s) of lep-5 expression. This project will enable Dr. Wontakal to gain expertise in genetic analysis, microscopy-based analysis, neurodevelopment, and non-coding RNAs. Importantly, the proposed project has the potential to serve as the foundation for starting his own independent research group. Clinically oriented training in neurogenetics, bioinformatics, and statistical genetics coupled with formal mentorship and leadership training will place Dr. Wontakal on a path to become a leader in genomic medicine.

项目概要/摘要 该提案概述了一个全面的五年指导职业发展计划，旨在为 候选人 Sandeep Wontakal，医学博士、哲学博士，作为一名医生从事独立学术研究职业—— 科学家。该培训计划旨在获得和完善三个关键方面的技能，这对于 作为一名医师科学家的成功职业生涯：1) 为独立研究项目奠定基础 2) 扩大临床专业知识，3) 增强指导/领导技能。他在功能领域的深厚背景 基因组学源于他的研究生工作以及他作为委员会认证的分子病理学家的经验，具有以下方面的专业知识 罕见疾病的基因组测试为培训计划奠定了坚实的基础。旺塔卡尔博士的 长期的研究和临床兴趣是解码非编码基因组中传输的信息并 这些区域的突变如何导致神经发育障碍。该提案的科学性 将由教授兼 HHMI 研究员 Oliver Hobert 博士指导，他是一位领先的神经科学家，拥有 指导成功学员的长期记录。 Wontakal 博士将进一步发展临床敏锐度来识别 在杰出人类遗传学家 David Goldstein 博士的指导下研究致病性非编码突变， 哥伦比亚大学基因组医学研究所所长。由知名医师组成的顾问小组—— 科学家和 RNA 神经生物学专家也将监督候选人的进展并提供指导。 这项工作将在哥伦比亚大学生物科学系的赞助下进行， 遗传学的发源地之一，病理学与细胞生物学系有着悠久的历史 培训医师科学家。哥伦比亚大学充满活力的科学和临床环境及其世界知名的 神经科学社区将成为成功执行拟议培训计划的理想环境。 Wontakal 博士将利用线虫中强大的遗传和细胞生物学工具进行研究 长非编码 RNA (lncRNA)、lep-5 如何在调节神经发育时间中发挥作用。 Lep-5 表达受到时间调节，初步结果表明lep-5是适当性成熟所必需的 男性神经系统。 Wontakal 博士已经培育出几种新菌株来确定如何精确地 通过研究以下三个目的建立lep-5的时空表达：1)确定顺式 控制lep-5表达的调控元件2)决定转录因子lin-14如何抑制lep- 5表达3)确定lep-5表达的转录激活因子。该项目将使博士。 Wontakal 获得遗传分析、基于显微镜的分析、神经发育和非编码方面的专业知识 RNA。重要的是，拟议的项目有可能成为他自己的项目的基础 独立研究小组。神经遗传学、生物信息学和统计遗传学方面的临床导向培训 加上正式的指导和领导力培训将使 Wontakal 博士走上成为领导者的道路。 基因组医学。