Shear stress is a major determinant of blood vessel remodeling and function, and play an important role in atherogenesis as atherosclerotic plaque forms exclusively in regions where flow departs from the laminar mode and become turbulent, independent of other risk factors. Despite its clinical and physiological significance, the mechanisms by which endothelial cells sense shear stress are poorly understood. Published and preliminary data suggest that both integrins and the Rho family GTPases Rho, Rac and Cdc42 participate in sensation of shear stress. Additional data indicate that integrins can regulate activity of Rho family GTPases. We ther3efore propose to test the hypothesis that integrins and Rho family GTPases mediate cellular responses to shear stress. These experiments will be accomplished using novel assays recently developed in my laboratory. 2) To investigate the roles of specific integrins and ligands in mediating cellular responses to mechanical stimuli. These experiments will define the integrin specificity of shear-induced events. 3) To determine whether Rho, Rac or Cdc42 are required for cellular responses to shear The effects of inhibitors of these pathways on shear responses will be tested to determine whether GTPases are necessary for cellular responses to shear. In some cases, activators of Rho, Rac or Cdc42 will be tested to determine if GTPase activation is sufficient to elicit the response. These experiments will define the roles of integrins and Rho family GTPases in cellular responses to shear, and may lead to the development of novel therapeutics that target these pathways to treat or prevent atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL048728-08
Application #
6202347
Study Section
Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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