Molecular Mechanisms of Neural Circuit Formation

神经回路形成的分子机制

• 批准号: 8996175
• 负责人: Miri Kerensa VanHoven
• 金额: $ 10.76万
• 依托单位: SAN JOSE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996175
• 关键词: Affect; Afferent Neurons; Animal Model; Animals; Axon; Behavior; Caenorhabditis elegans; Cells; Cues; Development; Developmental Biology; Foundations; Funding; Future; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Health; Human; Imaging Techniques; Immunoglobulins; International; Journals; Label; Length; Life; Ligands; Location; Maintenance; Manuscripts; Mediating; Mentors; Mission; Modality; Modeling; Molecular; Molecular Genetics; Morphology; National Institute of General Medical Sciences; Nervous System Trauma; Nervous system structure; Neuraxis; Neurites; Neurons; Pathway interactions; Peer Review; Perception; Prevention; Process; Proteins; Publishing; Research; Research Support; Role; Scientist; Secure; Signal Pathway; Signal Transduction; Spinal cord injury; Students; Testing; Therapeutic; Training; Underrepresented Students; Universities; Work; axon guidance; cell motility; disease diagnosis; gene discovery; insight; meetings; member; mutant; nervous system development; nervous system disorder; neural circuit; neuron development; next generation; novel; overexpression; receptor; research study; therapy development

DESCRIPTION (provided by applicant): The human central nervous system is composed of 100 billion neurons interconnected into precise circuits to mediate vital functions such as perception, thought, and behavior. A critical step in development of the nervous system is the outgrowth of axons, which are necessary for long-range transfer of information. However, it is equally important for axons to terminate outgrowth once they reach a target region. Much is known about cues required for axon outgrowth. Far less is known about the molecular signals neurons utilize to appropriately terminate axon outgrowth, and how this stable state is maintained. We propose to take advantage of the simple, well-characterized nervous system of C. elegans to elucidate the molecular mechanisms underlying this critical step in neural circuit formation. Understanding this process may aid in treating neurological disorders and nervous system injuries. This proposal is relevant to the NIGMS mission to support research that increases understanding of life processes, including the field of developmental biology, that lay the foundation for advances in disease diagnosis, treatment, and prevention, to train the next generation of scientists, and to develop and increase the diversity of the scientific workforce. To understand how axon outgrowth termination is mediated, we have developed a genetically encoded marker to fluorescently label neurites of the two PHB sensory neurons. This enables us to instantly assess axon length in live animals, allowing us to rapidly discover genes mediating this fundamental process using molecular, genetic, and imaging techniques. Using this marker, we have discovered that a conserved receptor and ligand previously studied for their role in guiding axon outgrowth, SAX-3/Robo and SLT-1/Slit, have novel roles in mediating axon outgrowth termination. Our research will characterize the mechanism of this new modality and define the pathway by which it is executed. Our specific aims are to: 1) characterize the role of SAX-3/Robo and SLT-1/Slit in axon outgrowth termination, 2) investigate the pathway by which SAX-3/Robo mediates axon outgrowth termination, and 3) characterize the role of SAX-3/Robo pathway members. The PI's short-term developmental objects are to 1) perform experiments described in this proposal, 2) present the findings at region, national, and international scientific meeting, and 3) publish manuscripts in leading, peer-reviewed journals. In the long-term, the PI's goal is to further the understanding of how neural circuits are formed and function in order to aid in the development of treatments for neurological disorders and spinal cord injuries. This MBRS SC3 will fund the research of approximately 16 undergraduates and 4 M.S. students over four years, including many underrepresented trainees at San Jos¿ State University, a primarily undergraduate and Masters-level university committed to training under-represented students. Undergraduates will perform the majority of the proposed work, with mentoring from M.S. students, a technician, and the PI. This funding would allow the PI to continue to develop a strong track record in research in order to secure future non-SCORE funding.

描述（由申请人提供）：人类中枢神经系统由1000亿个神经元组成，这些神经元相互连接成精确的回路，以调节感知、思维和行为等重要功能。神经系统发育的一个关键步骤是轴突的生长，这是长距离信息传递所必需的。然而，同样重要的是轴突一旦到达目标区域就终止生长。我们对轴突生长所需的线索了解很多。关于神经元用来适当终止轴突生长的分子信号，以及这种稳定状态是如何维持的，我们知之甚少。我们建议利用C. elegans来阐明神经回路形成中这一关键步骤的分子机制。了解这一过程可能有助于治疗神经系统疾病和神经系统损伤。这一建议与NIGMS的以下使命有关：支持旨在增进对生命过程的理解的研究，包括发育生物学领域，为疾病诊断、治疗和预防方面的进步奠定基础，培训下一代科学家，以及发展和增加科学工作队伍的多样性。到 为了了解轴突生长终止是如何介导的，我们已经开发了一种遗传编码的标记物来荧光标记两个PHB感觉神经元的神经突。这使我们能够立即评估活体动物的轴突长度，使我们能够使用分子，遗传和成像技术快速发现介导这一基本过程的基因。使用这个标记，我们已经发现，保守的受体和配体先前研究的作用，在指导轴突生长，SAX-3/Robo和Slit-1/Slit，有新的作用，在介导轴突生长终止。我们的研究将描述这种新模式的机制，并确定其执行的途径。我们的具体目标是：1）表征SAX-3/Robo和SAX-I/Slit在轴突生长终止中的作用，2）研究SAX-3/Robo介导轴突生长终止的途径，以及3）表征SAX-3/Robo途径成员的作用。PI的短期发展目标是：1）执行本提案中描述的实验; 2）在地区、国家和国际科学会议上展示研究结果; 3）在领先的同行评审期刊上发表手稿。在 从长远来看，PI的目标是进一步了解神经回路是如何形成和发挥作用的，以帮助开发神经系统疾病和脊髓损伤的治疗方法。这MBRS SC 3将资助大约16名本科生和4名硕士的研究。在四年多的时间里，有许多学生在圣何塞州立大学接受培训，其中包括许多代表性不足的学生，这是一所主要致力于培训代表性不足的学生的本科和硕士大学。本科生将执行大部分拟议的工作，从MS指导。学生，技术人员和PI。这笔资金将使PI能够继续在研究方面建立良好的记录，以确保未来的非SCORE资金。