Vascular smooth muscle cell (VSMC) phenotypes display remarkable heterogeneity in health and disease states. Yet the molecular mechanisms underlying modulation of VSMC phenotypes are not known. In Ang ll-stimulated VSMC model system, we find global changes in both the phosphoproteome and transcriptome. The cytoskeletal protein |3-actin is phosphorylated, leading to the hypothesis that phosphorylation could alter actin-dynamics, a process required for cell motility, growth and gene expression changes. Gene expression profiling indicated that several cell surface receptors, transcription regulators and proteins involved in organ damage are differentially expressed. Bioinformatics analysis of the promoter regions of these genes showed phylogenetically conserved DMAc/s-elements. We speculate that these genome regulatory elements bind transcriptional regulators, which are targets of Ang ll-induced signal transduction and alter gene expression. The short-term goals of this study are: (i) Identify phosphorylated protein targets in Ang ll-treated VSMCs by using immuno-purification and mass spectrometry (MS). We will test the network of phosphorylated proteins that modulate VSMC phenotype through gene expression changes, (ii) Determine site(s) of Ang ll- induced phosphorylation and the mechanism by which phosphorylation of p-actin affects VSMC proliferation, migration and gene expression, (iii) Define the molecular basis for Ang ll-responsiveness of genes. Our long-term goal is to understand regulation of VSMC function by angiotensin II (Ang II) and the molecular mechanism of phenotypic modulation of VSMC. Pathogenesis of major human diseases such as atherosclerosis and post-angioplasty restenosis involves VSMC phenotype switching.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083243-05
Application #
7780029
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$300,039
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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