The PAR-6/aPKC Polarity Complex in Synaptic Assembly and Function

突触组装和功能中的 PAR-6/aPKC 极性复合体

基本信息

批准号：
7642842
负责人：
Huaye Zhang
金额：
$ 9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642842
关键词：
Actins Address Affect Alzheimer&apos s Disease Behavioral Biochemical Biological Brain CNTNAP1 gene Caenorhabditis elegans Cell surface Cells Clinical Committee Members Complex Data Dendritic Spines Electrophysiology (science)Environment Excitatory Synapse Future Glutamate Receptor Glutamates Goals Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Knockout Mice Learning Maintenance Mass Spectrum Analysis Mediating Memory Memory impairment Mental Retardation Mentors Methods Molecular Morphogenesis Mus Nervous System Physiology Neurodegenerative Disorders Neurons PARD6A gene Pathway interactions Phase Phosphorylation Process Proteins Regulation Research Research Proposals Role Schizophrenia Signal Transduction Structure Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Translating Universities Vertebral column Virginia atypical protein kinase C base brain cell cognitive function human JTB protein in vivo insight nervous system disorder neurotransmission novel public health relevance response rho rho GTPase-activating protein synaptic function transmission process

项目摘要

This proposal is based on the finding that the PAR-6/aPKC polarity complex regulates dendritic spine morphogenesis, and that it does so through a novel pathway involving p190 RhoGAP and the RhoA GTPase. My goal during the mentored phase of this proposal is to learn electrophysiological approaches required to address whether the PAR-6/aPKC complex regulates synaptic function, and to extend my studies to an in vivo environment by generating a conditional PAR-6 knockout mouse. I will also learn the. mouse behavioral approaches to incoporate into my future research. The mentored phase research will be carried out in the University of Virginia. I will be mentored by Dr. Ian Macara (primary mentor), Dr. Suzanne Moenter (co-mentor), Dr. Julius Zhu and Dr. Scott Zeitlin (mentoring committee members). For the independent phase, I will continue to explore the function of the PAR-6/aPKC complex in synaptic assembly and function, both in dissociated neuronal cultures and in vivo. The specific questions that I would like to address during this phase are: What are the upstream regulators of the PAR-6/aPKC complex? What is the molecular basis for the activation of p190 RhoGAP by PAR-6/aPKC? Is PAR-6 involved in synaptic plasticity and memory formation in vivo? Together, these studies will provide significant insight into the role of the PAR-6/aPKC complex in regulating synaptic function. My long term goal is to understand the complex signaling mechanisms regulating synaptic assembly and function, and how they relate to memory formation in vivo. I will use a combination of cell biological, electrophysiological and behavioral approaches to address these questions. PUBLIC HEALTH RELEVANCE: The goal of this research proposal is to understand the effects of a group of proteins called PAR-6 and aPKC on the way brain cells connect with each other. The results can have significant implications in various neurological disorders including mental retardation, schizophrenia and Alzheimer's disease.

该提议基于以下发现：PAR-6/aPKC 极性复合物调节树突棘形态发生，并且它通过涉及 p190 RhoGAP 和 RhoA GTPase 的新途径来实现这一点。在本提案的指导阶段，我的目标是学习解决 PAR-6/aPKC 复合物是否调节突触功能所需的电生理学方法，并通过生成条件性 PAR-6 基因敲除小鼠将我的研究扩展到体内环境。我也来学习一下。小鼠行为方法纳入我未来的研究。指导阶段研究将在弗吉尼亚大学进行。我将受到 Ian Macara 博士（主要导师）、Suzanne Moenter 博士（共同导师）、Julius Zhu 博士和 Scott Zeitlin 博士（导师委员会成员）的指导。对于独立阶段，我将继续探索 PAR-6/aPKC 复合物在分离神经元培养物和体内的突触组装和功能中的功能。在此阶段我想解决的具体问题是：PAR-6/aPKC 复合体的上游调节因子是什么？ PAR-6/aPKC 激活 p190 RhoGAP 的分子基础是什么？ PAR-6 是否参与体内突触可塑性和记忆形成？总之，这些研究将为 PAR-6/aPKC 复合物在调节突触功能中的作用提供重要的见解。我的长期目标是了解调节突触组装和功能的复杂信号机制，以及它们与体内记忆形成的关系。我将结合使用细胞生物学、电生理学和行为学方法来解决这些问题。公共健康相关性：本研究计划的目标是了解一组名为 PAR-6 和 aPKC 的蛋白质对脑细胞相互连接方式的影响。研究结果可能对各种神经系统疾病（包括精神发育迟滞、精神分裂症和阿尔茨海默病）产生重大影响。