The hypothesis of this proposal is that the RGS 16 protein is an integral component of the G-alpha-q/11 signaling complex, serving as a feedback inhibitor of G-alpha-q/11 signaling in stressed cardiomyocytes, thus helping to maintain cardiac homeostasis. We propose that a point mutation in the RGS box of RGS16 (D179Y) found in patients with dilated cardiomyopathy alters the conformation of the interaction surface with G-alpha-q/11 and/or other proteins in the signaling complex, rendering RGS16 D179Y to function as a dominant negative protein, ultimately contributing to dilated cardiomyopathy. To test this hypothesis, we shall explore the following specific aims:
Aim 1. We shall examine the GAP and potential dominant negative activity of D179Y and wild type RGS16 proteins in several in vitro assays, including single-turnover assays, transition-state analog binding assays, and G-alpha-q -Coupled steady state assays, and G-alpha-q -coupled MAPK activation;
Aim 2. We will overexpress D179Y and RGS 16 proteins specifically in cardiomyocytes by employing the alpha-MHC promoter in transgenic mice and then characterize the onset of cardiomyocytes hypertrophy;
Aim 3. We will create Rgs 16 D179Y knock-in mice and characterize the onset of dilated cardiomyopathy;
Aim 4. We will continue to screen cardiac patients and healthy individuals to identify additional Rgs mutation. The primary objective of this proposal is to evaluate the causative role of the D179Y allele of RGS16 in the progression of dilated cardiomyopathy. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL072551-03
Application #
6833417
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Meadows, Tawanna
Project Start
2003-01-01
Project End
2005-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143