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.
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.
