Mapping Brainstem Motor Neuron Subtypes and Genetic Pathways Involved in their Differential Susceptibility to Disease

绘制脑干运动神经元亚型及其对疾病的不同易感性所涉及的遗传途径

基本信息

批准号：
10064032
负责人：
Matthew F Rose
金额：
$ 15.56万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064032
关键词：
ATAC-seq Advisory Committees Affect Amyotrophic Lateral Sclerosis Anatomy Axon Biological Models Boston Brain Stem Breathing Cell Culture Techniques Cell Nucleus Cephalic Characteristics Clinical Data Data Analyses Development Developmental Gene Discipline Disease Duane Retraction Syndrome Enhancers Extracellular Matrix Eye Development Eye Movements Facial Expression Fellowship Foundations Functional disorder Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Heterogeneity Genetic Transcription Goals Growth Health Heterogeneity Hospitals Human Genetics Image Investigation Label Laboratories Lead Location Maps Mediating Mentors Modeling Molecular Biology Motor Motor Neuron Disease Motor Neurons Movement Mus Muscle Nerve Neuroanatomy Neurology Neurons Oculomotor nucleus Pathologic Pathology Pathway interactions Pattern Pediatric Hospitals Peripheral Physicians Population Population Heterogeneity Predisposition Regulator Genes Reporter Reproducibility Research Research Personnel Residencies Scientist Speech Spinal System Technology Testing Time Tissues Training Training Programs United States National Institutes of Health Woman Work axon growth axon guidance career career development clinical phenotype design disease-causing mutation experience imaging approach medical schools meetings motor neuron development mouse genetics mouse model nerve supply nervous system disorder neurogenetics neuron development neuropathology oculomotor professor programs senior faculty single-cell RNA sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT This NIH K08 proposal describes a five-year training program for career development in academic neuropathology and developmental neurogenetics. Dr. Matthew Rose has completed clinical residency in Anatomic Pathology and fellowship in Neuropathology at Brigham and Women’s Hospital (BWH) and Boston Children’s Hospital (BCH) at Harvard Medical School (HMS), and will embark on a research program designed to train for an independent academic career in neurologic disease-oriented research. In this training program, Dr. Rose will acquire in-depth experience in the study of ocular motor neuron (OMN) development and axon targeting, interpretation of single cell RNA-sequencing, analysis of gene regulatory networks, tissue clearing and advanced imaging approaches, and gene-editing technologies. His mentor, Dr. Elizabeth Engle (a Professor of Neurology and HHMI Investigator at BCH), is a leader in brainstem OMN development and congenital cranial dysinnervation disorders (CCDDs) that involve these motor neurons. Her laboratory has extensive experience in human and mouse genetics, neuroanatomy, large data analyses, molecular biology, imaging, and cell culture techniques. She has an established track record for mentoring other trainees to successful careers in biomedical investigation. In addition to his mentor, he has assembled a group of collaborators with complementary expertise in these disciplines, and an Advisory Committee of senior faculty with extensive experience in guiding physician-scientists through the transition to independence. He will supplement this training with didactics and presentation of work at national meetings. The primary scientific goal of the proposed research plan is to study normal and abnormal OMN specification and axonal growth and guidance in health and disease. Dr. Rose provides an initial map of the genetic differences among brainstem motor neurons that may serve as a foundation for further studies of all motor neuron diseases. These preliminary data will be used as a foundation to further study the development of the OMN subnuclei by discovering markers of each OMN subpopulation, and then applying those markers to the study of the CCDDs. The central hypothesis of this proposal is that the differences in gene expression among OMN subpopulations may predispose certain subtypes to undergo dysinnervation in different CCDDs. Single cell RNA-seq will be performed on the three primary OMNs: the oculomotor, trochlear, and abducens brainstem nuclei, in order to discover markers of each subpopulation. In combination with ATAC-seq, the transcriptional regulatory networks for OMN specification will be investigated. Unique markers of each OMN subpopulation will then be used to study normal OMN axon projections to distinct muscle targets, as well as using them to dissect the contributions of different populations to the stereotypic and pathologic aberrant innervations observed in the CCDDs. These studies have significance to the broader fields of neuronal specification and differentiation and to axonal growth and guidance.

项目概要/摘要 NIH K08 提案描述了一项为期五年的学术职业发展培训计划 Matthew Rose 博士已完成神经病理学和发育神经遗传学的临床住院实习。布莱根妇女医院 (BWH) 和波士顿的解剖病理学和神经病理学研究员哈佛医学院 (HMS) 儿童医院 (BCH) 将开展一项旨在为神经系统疾病研究的独立学术生涯提供培训。在本次培训中，Rose博士将深入了解眼运动神经元（OMN）的研究发育和轴突靶向、单细胞 RNA 测序解释、基因调控分析他的导师 Dr. Elizabeth Engle（神经病学教授和 BCH 的 HHMI 研究员）是脑干 OMN 领域的领导者涉及这些运动神经元的发育和先天性颅神经失调障碍（CCDD）。实验室在人类和小鼠遗传学、神经解剖学、大数据分析、她在指导他人方面有着良好的记录。除了他的导师之外，他还组建了一个团队，帮助学员在生物医学研究领域取得成功。由在这些学科具有互补专业知识的合作者组成，以及由高级教师组成的咨询委员会他将在指导向独立过渡方面拥有丰富的医师科学家经验。通过教学和在国家会议上介绍工作来补充这种培训。拟议研究计划的主要科学目标是研究正常和异常的 OMN 规范罗斯博士提供了轴突生长以及健康和疾病方面的初步图谱。脑干运动神经元之间的差异可以作为进一步研究所有运动神经元的基础这些初步数据将作为进一步研究OMN发展的基础。通过发现每个 OMN 亚群的标记，然后应用这些标记来研究亚核该提案的中心假设是 OMN 之间基因表达的差异。亚群可能会使某些亚型在不同的 CCDD 中发生神经失调。将在三个主要 OMN 上进行单细胞 RNA 测序：动眼神经、滑车和外展神经脑干细胞核，以便与 ATAC-seq 结合发现每个亚群的标记。将研究 OMN 规范的转录调控网络。然后，亚群将用于研究正常的 OMN 轴突投射到不同的肌肉目标，以及用它们来剖析不同人群对刻板印象和病理异常的贡献这些研究对更广泛的神经领域具有重要意义。规范和分化以及轴突生长和引导。