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: 10706942
• 负责人: Matthew F Rose
• 金额: $ 23.98万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706942
• 关键词: Mapping; Brainstem; Motor; Neuron; Subtypes

PROJECT SUMMARY/ABSTRACT This NIH K08 proposal describes an initial five-year training program with one year extension 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 initial mentor at BCH, 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. With Dr. Rose’s move to the University of California, Irvine (UCI), Albert La Spada, MD, PhD at UCI will become Dr. Rose’s mentor, and Dr. Engle will continue as his co-mentor. Both have established track records for mentoring 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 at UCI with extensive experience in guiding physician- scientists through the transition to independence. 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 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.

项目摘要/摘要 该NIH K08提案描述了一项最初的五年培训计划，并延长了职业 学术神经病理学和发育神经遗传学的发展。马修·罗斯博士已经完成 Brigham和妇女医院的解剖病理学和奖学金的临床居留 （BWH）和哈佛医学院（HMS）的波士顿儿童医院（BCH），并将进行研究 计划旨在培训以神经疾病为导向的研究的独立学术职业。 在这个培训计划中，罗斯博士将在眼部运动神经元研究中获得深入的经验（OMN） 开发和轴突靶向，单细胞RNA测序的解释，基因调节的分析 网络，组织清除和高级成像方法以及基因编辑技术。他最初的精神 在BCH，伊丽莎白·恩格尔（Elizabeth Engle 涉及这些运动神经元的OMN发育和先天性颅骨功能障碍障碍（CCDDS）。 罗斯博士搬到加利福尼亚大学尔湾分校（UCI），艾伯特·拉斯帕达（Albert La Spada），医学博士，博士，UCI Will 成为罗斯博士的精神，恩格尔博士将继续担任他的同事。 两者都为心理学学员建立了记录，从事生物医学调查的成功职业。 除了他的心理外，他还组建了一群合作者，具体专业知识 学科，以及UCI高级教师的咨询委员会，在指导医师方面拥有丰富的经验 科学家通过过渡到独立性。 拟议的研究计划的主要科学目标是研究正常和异常OMN规范 以及轴突生长和健康和疾病的指导。罗斯博士提供了通用的初始地图 脑干运动神经元之间的差异，可以作为所有运动神经元的进一步研究的基础 疾病。这些初步数据将被用作进一步研究OMN的发展的基础 通过发现每个OMN亚群的标记，然后将这些标记应用于研究 CCDD。该提议的中心假设是OMN基因表达的差异 亚群可能会使某些亚型容易在不同的CCDD中发生功能障碍。 单细胞RNA-seq将在三个主要OMN上进行：动眼运动，Trochlear和Bbducens 脑干核发现每个亚群的标记。结合ATAC-SEQ，转录 将研究用于OMN规范的监管网络。每个OMN亚群的独特标记将 然后用于研究普通的OMN轴突项目以不同的肌肉目标，并使用它们进行剖析 不同人群对刻板印象和病理异常神经的贡献 CCDD。这些研究对神经元规范和分化的更广泛领域具有重要意义。 轴突生长和指导。