Molecular Mechanisms of Neural Circuit Formation

神经回路形成的分子机制

• 批准号: 8842653
• 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/8842653
• 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; Publishing; Research; Research Support; Role; Scientist; Secure; Signal Pathway; Signal Transduction; Spinal cord injury; Students; Testing; Therapeutic; Training; 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; robo protein; 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(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电路，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，轴突是远程信息传输所必需的。然而，轴突一旦到达目标区域就终止生长，这一点同样重要。关于轴突生长所需的线索，我们知道得很多。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，人们知道的要少得多。我们建议利用线虫简单的、特征良好的神经系统来阐明神经回路形成这一关键步骤背后的分子机制。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。这项建议与NIGMS的任务有关，该任务旨在支持增加对包括发育生物学领域在内的生命过程的了解的研究，为疾病诊断、治疗和预防方面的进展奠定基础，培训下一代科学家，并发展和增加科学劳动力的多样性。至 为了了解轴突生长终止是如何介导的，我们开发了一个基因编码的标记物来荧光标记两个PHB感觉神经元的神经突起。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参与这一基本过程的基因。利用这个标记，我们发现了一个先前研究过的引导轴突生长的保守受体和配体，SAX-3/Robo和SLT-1/Sit，在介导轴突生长终止方面具有新的作用。我们的研究将描述这一新模式的机制，并确定其执行的途径。我们的具体目标是：1)研究SAX-3/Robo和SLT-1/Sit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；3)研究SAX-3/Robo通路成员的作用。PI的短期发展目标是：1)进行本建议中描述的实验；2)在地区、国家和国际科学会议上展示研究结果；3)在领先的同行评议期刊上发表手稿。在……里面 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，以帮助开发神经疾病和脊髓损伤的治疗方法。MBRS SC3将在四年内资助大约16名本科生和4名硕士研究生的研究，其中包括圣何塞州立大学的许多代表不足的实习生，圣何塞州立大学是一所主要致力于培养代表不足的学生的本科和硕士水平的大学。本科生将完成大部分拟议的工作，并由理工科学生、一名技术员和PI提供指导。这笔资金将使PI能够继续发展强大的研究记录，以确保未来的非计分资金。