Regulation of synaptic specificity by two Ig-domain containing families

两个含有 Ig 结构域的家族对突触特异性的调节

基本信息

批准号：
9130929
负责人：
Matthew Yasuo Pecot
金额：
$ 22万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130929
关键词：
Address Affect Afferent Neurons Architecture Axon Behavior Binding Biomedical Research Brain Cells Cellular biology Communication Complex Defect Dendrites Department chair Development Development Plans Disease Drosophila genus Electron Microscopy Environment Epilepsy Eye Faculty Family Future Gene Targeting Genes Genetic Goals Growth Health Human Immunoglobulin Domain Immunoglobulins In Vitro Individual Intellectual functioning disability Invertebrates Investigation Knowledge Learning Light Mentors Methods Molecular Motion Multiple Partners Muscle Nervous System Physiology Nervous system structure Neurobiology Neurons Neurosciences Research Optic Lobe Pattern Photoreceptors Process Proteins Regulation Research Research Design Research Personnel Role Schizophrenia Sensory Specificity Stereotyping Synapses Synaptic Potentials Testing Therapeutic Vertebrates Visual system structure autism spectrum disorder axon guidance base career career development cell type collaborative environment design experience fly gain of function in vivo light microscopy medical schools member mid-career faculty nervous system disorder neural circuit neuron development novel parallel processing professor programs relating to nervous system research study response skills synaptogenesis tool visual information

项目摘要

DESCRIPTION (provided by applicant): The nervous system comprises tremendous cellular complexity yet its function relies on neurons forming precise patterns of synaptic connections. How individual neurons find and form synapses with the correct partners amidst so many inappropriate ones remains poorly understood. Recent evidence indicates that defects in neural connectivity are an underlying cause of neurological disorders. Thus, identifying molecular mechanisms underlying synaptic connectivity is of major importance to biomedical research and human health. Within the visual systems of vertebrates and invertebrates neurons target axons or dendrites to discrete layers wherein they form synaptic connections, thereby providing a structural basis for the parallel processing of different visual information. In the fly optic lobe synaptic layers contain synapses from many neurons, yet specific neurons within a layer synapse with only a subset of these. How synaptic specificity within layers is achieved is unknown. We have discovered that two families of immunoglobulin (Ig) domain-containing proteins known to engage in heterothallic inter-family interactions are expressed complementarily in a cell-type and layer-specific manner within the fly optic lobe. Different afferent cell types express unique combinations of Dprs (21 genes), and target neurons express Dpr interacting proteins or DIPs (11 members). We hypothesize that different heterothallic Dpr-DIP interactions provide a common mechanism by which afferent neurons establish unique patterns of synaptic connections. To test this hypothesis we will investigate Dpr and DIP function in regulating synaptic specificity within a single afferent cell type, L3 lamina monopolar neurons which synapse with multiple partners within their target layer. We will identify cognate Dpr-DIP pairs expressed by L3 neurons and their synaptic partners and investigate their role in synapse formation. We will also perform gain of function experiments to assess if these Dpr-DIP interactions are sufficient to promote synaptic connectivity. The goal of this research is to identify a molecular strategy underlying synaptic specificity. These studies are designed to address a fundamental gap in our knowledge of the molecular mechanisms underlying neural connectivity and establish a platform for the long term investigation of this issue. We anticipate this research will shed light on strategies for rewiring neural circuits in individuals affected by neurological disease and for creating neural circuits with novel functions. To achieve my short term career goal of establishing an independent research program and earning promotion to Associate Professor in the Department of Neurobiology at Harvard Medical School, and my long term career goal of achieving tenure within the Department, I have assembled a team of mentors consisting of tenured faculty at Harvard Medical School who have helped me establish a career development plan. David Ginty, a Professor in the Department of Neurobiology will serve as my primary mentor, and Michael Greenberg, Professor and Chair of the Department of Neurobiology, and David Van Vactor, Professor in the Department of Cell Biology will be co-mentors. Each member will contribute to my growth as an independent investigator in complementary ways based on their scientific expertise and experience. My career development activities will be focused on: (1) Improvement of mentoring, management and lab organization skills (2) Development of my research program (3) Learning how to best fulfill my institutional responsibilities. Based on my strong career development plan, the expertise of my mentor team and the supportive environment within the Department of Neurobiology and Harvard Medical School I believe I have an excellent opportunity to achieve my career goals.

描述（由申请人提供）：神经系统包含巨大的细胞复杂性，但其功能依赖于形成精确的突触连接模式的神经元如何在如此多的不合适的突触中找到并形成正确的突触，目前仍知之甚少。神经连接缺陷是神经系统疾病的根本原因，因此，识别突触连接的分子机制对于生物医学研究和人类健康具有重要意义。或树突到离散层，以便它们形成突触连接，从而为不同视觉信息的并行处理提供结构基础。我们发现，已知参与异菌家族间相互作用的两个含有免疫球蛋白（Ig）结构域的蛋白质家族是互补表达的。不同的传入细胞类型表达 Dpr（21 个基因）的独特组合，并且目标神经元表达 Dpr 相互作用蛋白或 DIP（11 个成员）。相互作用提供了一种共同机制，传入神经元通过该机制建立独特的突触连接模式。为了检验这一假设，我们将研究 Dpr 和 DIP 在调节单一传入细胞类型 L3 内的突触特异性方面的功能。单极层我们将识别 L3 神经元及其突触伙伴表达的同源 Dpr-DIP 对，并研究它们在突触形成中的作用。我们还将进行功能增益实验来评估这些 Dpr-DIP 是否存在。这项研究的目的是确定突触特异性的分子策略，旨在解决我们对神经连接分子机制的认识上的根本差距，并为长期研究建立一个平台。我们预计这项研究将揭示重新连接受此问题影响的个体神经回路的策略。为了实现我的短期职业目标，即建立一个独立的研究项目并晋升为哈佛医学院神经生物学系的副教授，以及我的长期职业目标，即在哈佛医学院获得终身教职。在该系，我组建了一个由哈佛医学院终身教授组成的导师团队，他们帮助我制定了职业发展计划，神经生物学系教授大卫·金蒂（David Ginty）将担任我的主要导师，迈克尔·格林伯格（Michael Greenberg）教授将担任我的主要导师。和系主任神经生物学和细胞生物学系教授 David Van Vactor 将作为共同导师，根据他们的科学专业知识和经验，以互补的方式为我的成长做出贡献。： (1) 提高指导、管理和实验室组织技能 (2) 制定我的研究计划 (3) 基于我强大的职业发展计划、导师团队的专业知识和支持，学习如何最好地履行我的机构职责。神经生物学系和哈佛医学院内的环境我相信我有一个绝佳的机会来实现我的职业目标。