Activity-Dependent Regulation of Synapses by Shank

柄对突触的活动依赖性调节

基本信息

批准号：
6928559
负责人：
ALBERT Y HUNG
金额：
$ 12.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6928559
关键词：
actin binding protein dendrites developmental neurobiology electrostimulus gene targeting genetically modified animals glutamate receptor laboratory mouse learning membrane proteins memory nerve /myelin protein neural transmission neurogenesis neurogenetics protein localization protein protein interaction protein structure function

项目摘要

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.

描述（由申请人提供）：该项目的目的是调查新发现的突触后蛋白Shank在调节中的作用树突状脊柱形态和细胞骨架。局部电刺激诱导树突状刺的生长，表明突触活动直接调节神经元结构和电路。这些分子基础活动依赖性变化尚不清楚，但可能涉及突触后的与受体和/或细胞骨架元素相互作用的蛋白质。尚克的行为作为多种谷氨酸受体亚型的推定支架，也结合依次与动态有关细胞骨架重排，并易位为突触谷氨酸。这项研究检查了尚克在树突状调节中的作用刺及其在体内功能通过三个特定目标。首先a 细胞生物学，生化和主要抑制方法的结合将用于确定谷氨酸管制的cortactin的机制转运到突触，并确定尚克托替替丁素的相互作用是否为此响应需要。第二，尚克如何诱导脊柱生长通过结构功能分析研究。最后，一种遗传方法，一代 shank1“敲除”小鼠的小鼠将用于调查尚克的作用大脑发育中的蛋白质，突触后受体组织和学习和记忆。候选人的长期目标是了解异常突触传播导致神经系统疾病。突触是大脑的信号处理单元，并通过谷氨酸被认为在急性神经元损伤中都起作用（例如中风和癫痫发作）和慢性神经退行性疾病（包括亨廷顿氏病，帕金森氏病和肌萎缩性侧索硬化症）。了解突触后蛋白（例如柄）如何调节活动依赖性突触可塑性可能会阐明谷氨酸的机制毒性。直接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的技术神经生物学，由摩根·尚（Morgan Sheng）博士赞助，这将使他成为一名生产性，独立的分子神经科医生。