The proposal is based on the finding that the PAR-6/aPKC complex regulates dendritic spine morphogenesis, and it does so through a novel signaling pathway involving pi90 RhoGAP and the RhoA GTPase. Studies during the mentored phase of this project revealed the small GTPase Rnd1 as a candidate protein for mediating the effects of PAR-6/aPKC on p190RhoGAP and RhoA.
Aim 1 of this proposal seeks to elucidate the molecular mechanism by which the PAR-6/aPKC complex regulates Rndl. Specifically, the effect of the PAR complex on Rndl expression and phosphorylation, and Rnd/190 interaction will be examined. To further examine the role of the PAR complex in synaptic function, we will elucidate the mechanisms by which the PAR complex regulates glutamatergic synaptic transmissioin, and identify the upstream regulators of the PAR complex. Finally, we are generating PAR-6C conditional knockout mice to test the hypothesis that the PAR complex is involved in synaptic plasticity and memory formation in vivo. My long term goal is to understand the complex signaling mechanisms regulating dendritic spine morphogenesis and synaptic plasticity, and how they translate to memory formation and maintenance in vivo.

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 communicate with each other. The results can have significant implications in various neurological disorders including mental retardation, schizophrenia and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
7R00NS065183-06
Application #
8704179
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mamounas, Laura
Project Start
2009-05-01
Project End
2014-12-31
Budget Start
2013-07-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2013
Total Cost
$161,145
Indirect Cost
$57,847
Name
Rbhs-Robert Wood Johnson Medical School
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854