Regulation of synaptic specificity by two Ig-domain containing families

 描述(申请人提供)：神经系统由巨大的细胞复杂性组成，但其功能依赖于神经元形成精确的突触连接模式。在这么多不合适的伙伴中，单个神经元是如何找到正确的伙伴并与之形成突触的，目前还知之甚少。最近的证据表明，神经连通性缺陷是神经功能障碍的一个潜在原因。因此，识别突触连接的分子机制对生物医学研究和人类健康具有重要意义。在脊椎动物和无脊椎动物的视觉系统中，神经元将轴突或树突作为目标，在不同的层中形成突触连接，从而为不同视觉信息的并行处理提供结构基础。在苍蝇视叶中，突触层包含来自许多神经元的突触，但层内特定的神经元只与这些突触的一个子集突触。层内突触的特异性是如何实现的尚不清楚。我们发现，两个已知参与异型家族间相互作用的免疫球蛋白(Ig)结构域蛋白家族在苍蝇视叶内以细胞型和层特异性的方式互补表达。不同类型的传入细胞表达DPR的独特组合(21个基因)，靶神经元表达DPR相互作用蛋白或DIP(11个成员)。我们假设，不同的异位DPR-DIP相互作用提供了一个共同的机制，通过这种机制，传入神经元建立了独特的突触连接模式。为了验证这一假设，我们将研究DPR和DIP在调节单个传入细胞类型L3单极板内突触特异性方面的功能。 在其目标层内与多个伙伴突触的神经元。我们将鉴定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，以评估这些DPR-DIP相互作用是否足以促进突触连接。这项研究的目的是确定突触特异性的分子策略。这些研究旨在解决我们对神经连接潜在的分子机制的认识上的根本差距，并为这一问题的长期研究建立一个平台。我们预计，这项研究将有助于阐明受艾滋病影响的个体重新连接神经回路的策略。 神经疾病和创造具有新功能的神经电路。为了实现我建立独立研究项目并晋升为哈佛医学院神经生物学系副教授的短期职业目标和在系内实现终身教职的长期职业目标，我组建了一个由哈佛医学院终身教职员工组成的导师团队，他们帮助我制定了职业发展计划。神经生物学系教授大卫·金蒂将担任我的主要导师，神经生物学系教授兼主任迈克尔·格林伯格和细胞生物学系教授大卫·范·瓦泰尔将担任共同导师。每个成员都将以他们的科学专长和经验为基础，以互补的方式为我作为独立调查员的成长做出贡献。我的职业发展活动将集中在：(1)提高指导、管理和实验室组织技能(2)发展我的研究计划(3)学习如何最好地履行我的机构责任。基于我良好的职业发展计划，我的导师团队的专业知识，以及神经生物系和哈佛医学院内部的支持环境，我相信我有一个实现我职业目标的绝佳机会。

 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.