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

• 批准号: 10416623
• 负责人: Matthew F Rose
• 金额: --
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/10416623
• 关键词: Mapping; Brainstem; Motor; Neuron; Subtypes

Contact PD/PI: Rose, Matthew F 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. Project Summary/Abstract Page 6

联系PD/PI：Rose、Matthew F 项目总结/摘要 NIH K 08提案描述了一项为期五年的学术职业发展培训计划， 神经病理学和发育神经遗传学。马修·罗斯博士已完成临床实习， 布里格姆妇女医院（BWH）和波士顿的解剖病理学和神经病理学奖学金 儿童医院（BCH）在哈佛医学院（HMS），并将着手研究计划， 在神经系统疾病导向研究中培养独立的学术生涯。 在这个培训项目中，Rose博士将获得眼运动神经元（OMN）研究的深入经验 发育和轴突靶向，单细胞RNA测序的解释，基因调控分析， 网络，组织清除和先进的成像方法，以及基因编辑技术。他的导师，博士。 Elizabeth Engle（BCH神经学教授和HHMI研究员）是脑干OMN的领导者 发育和先天性颅神经支配障碍（CCDD），涉及这些运动神经元。她 实验室在人类和小鼠遗传学，神经解剖学，大数据分析， 分子生物学、成像和细胞培养技术。她在指导其他人方面有着良好的记录， 学员成功的职业生涯中的生物医学调查。除了他的导师，他还召集了一群 在这些学科中具有互补专业知识的合作者，以及由高级教师组成的咨询委员会 在指导医生-科学家向独立过渡方面拥有丰富的经验。他将 用教学法和在国家会议上介绍工作来补充这种培训。 研究计划的主要科学目标是研究正常和异常OMN规范 以及轴突的生长和健康疾病的指导。罗斯博士提供了一个初步的遗传图谱， 脑干运动神经元之间的差异，可作为进一步研究所有运动神经元的基础 疾病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亚群的标记物，然后将这些标记物应用于OMN亚群的研究， 的CCD。该建议的中心假设是，OMN中基因表达的差异 亚群可能使某些亚型在不同的CCDD中易发生神经支配障碍。 单细胞RNA-seq将在三个主要的OMN上进行：眼神经、眼轮匝肌和外展神经 脑干核，以发现每个亚群的标记物。与ATAC-seq组合， 将研究OMN特化的转录调控网络。每个OMN的唯一标记 亚群然后将用于研究正常OMN轴突投射到不同的肌肉靶点，以及 用它们来剖析不同人群对刻板和病理性异常的贡献， 在CCD中观察到的神经支配。这些研究对神经元的更广泛领域具有重要意义。 规范和分化以及轴突生长和指导。 项目摘要/摘要第6页