Activity-Dependent Regulation of Synapses by Shank

描述(由申请人提供)：本项目的目标是调查 一种新发现的突触后蛋白Shank在调节中的作用 树突棘的形态和细胞骨架。局部电刺激 诱导树突棘的生长，表明突触活动直接调节神经元的结构和电路。这些的分子基础 依赖活动的改变尚不清楚，但可能涉及突触后 与受体和/或细胞骨架元件相互作用的蛋白质。小腿动作 作为多种谷氨酸受体亚型的假定支架，还结合 与放射结合蛋白Cortactin有关，该蛋白与动力学有关 细胞骨架重排和移位到突触的反应 谷氨酸。本研究探讨了Shank在树突状细胞的调控中的作用。 脊椎及其在体内的功能通过三个特定的目的。第一个a 结合细胞生物学、生化和显性抑制方法 将被用来确定谷氨酸调节的皮质蛋白的机制 易位到突触，并确定Shankcortactin相互作用是否 此响应需要。第二，尚克如何促进脊椎生长 通过结构功能分析进行了研究。最后，一种遗传方法，世代 将被用来研究Shank的角色 蛋白质在脑发育、突触后受体组织和 学习和记忆。候选人的长期目标是了解如何 突触传递的异常会导致神经系统疾病。突触是 大脑的信号处理单元，以及突触的过度兴奋 谷氨酸被认为在急性神经元损伤(如 中风和癫痫)和慢性神经退行性疾病(包括 亨廷顿病、帕金森氏病和肌萎缩侧索硬化症)。 了解突触后蛋白，如Shank，如何调节 依赖活性的突触可塑性可能有助于揭示谷氨酸的作用机制 毒性。眼下的目标是获得最新的培训 分子遗传学、蛋白质生物化学和细胞学技术 神经生物学，由摩根·盛博士赞助，这将使他成为一名 多产、独立的分子神经学家。

DESCRIPTION (provided by applicant): The goal of this project is to investigate the role of a newly discovered postsynaptic protein, Shank, in the regulation of dendritic spine morphology and cytoskeleton. Local electrical stimulation induces growth of dendritic spines, suggesting that synaptic activity directly modulates neuronal architecture and circuitry. The molecular basis for these activitydependent changes is not known, but probably involves postsynaptic proteins that interact with receptors and/or cytoskeletal elements. Shank acts as a putative scaffold for multiple glutamate receptor subtypes and also binds to the actinbinding protein cortactin, which has been implicated in dynamic cytoskeletal rearrangement and translocates to synapses in response to glutamate. This study examines the role of Shank in the regulation of dendritic spines and its in vivo function through three specific aims. First a combination of cell biological, biochemical, and dominant inhibitory approaches will be used to determine the mechanism for glutamateregulated cortactin translocation to synapses, and to identify if Shankcortactin interaction is required for this response. Second, how Shank induces spine growth will be studied by structurefunction analysis. Finally, a genetic approach, generation of a Shank1 "knockout" mouse, will be used to investigate the role of Shank proteins in brain development, in postsynaptic receptor organization, and in learning and memory. The longterm goal of the candidate is to understand how aberrant synaptic transmission contributes to neurologic disease. Synapses are the signal processing units of the brain, and overexcitation of synapses by glutamate is thought to play a role in both acute neuronal injury (such as stroke and seizure) and chronic neurodegenerative conditions (including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis). Understanding how postsynaptic proteins, such as Shank, regulate activitydependent synaptic plasticity may shed light on mechanisms of glutamate toxicity. The immediate goal is to obtain training in the most uptodate techniques in molecular genetics, protein biochemistry, and cellular neurobiology, sponsored by Dr. Morgan Sheng, which will enable him to become a productive, independent molecular neurologist.