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

这一提议是基于PAR-6/aPKC极性复合物调节树突棘形态发生的发现，并且它通过涉及p190 RhoGAP和RhoA GT3的新途径来实现。我的目标在指导阶段的建议是学习电生理学方法，以解决是否PAR-6/aPKC复合物调节突触功能，并延长我的研究，以在体内环境中产生一个条件PAR-6敲除小鼠。我也会学习的。老鼠行为学的研究方法来融入我未来的研究。指导阶段的研究将在弗吉尼亚大学进行。我将由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（指导委员会成员）指导。对于独立的阶段，我将继续探索PAR-6/aPKC复合物在突触组装和功能，无论是在分离的神经元培养物和在体内的功能。在此阶段，我想解决的具体问题是：PAR-6/aPKC复合物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，以及它们如何与体内记忆形成相关。我将结合细胞生物学、电生理学和行为学的方法来解决这些问题。公共卫生相关性：这项研究计划的目标是了解一组称为PAR-6和aPKC的蛋白质对脑细胞相互连接方式的影响。该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有重要意义。

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.