Role of the GRK/beta-arrestin system in atheroscelrosis

Duke University, Durham NC

Investigators

Abstract

DESCRIPTION (provided by applicant): This research to be conducted during the period of the NRSA fellowship aims to elucidate mechanisms underlying the regulation of cellular chemotaxis in the setting of atherosclerosis. Specifically, experiments will focus on testing the hypothesis that two molecular families, GRKs and beta-arrestins, are critically involved in the regulation of chemotaxis of monocyte, lymphocytes, and vascular smooth muscle cells. Both in vitro and in vivo approaches will be utilized. One set of experiments (see Specific Aim #1) implements an in vitro Strategy to examine the roles of GRKs and beta-arrestins in chemotaxis, using mutant mice genetically deficient in specific GRKs and beta-arrestins, and constructs encoding various gain or loss-of-function mutant GRKs and beta-arrestins, to characterize the biochemical events associated with chemotaxis and to ascertain the roles of GRKs/beta-arrestins in this process. The second set of experiments (see Specific Aim #2) employs a murine model of atherosclerosis-like disease (neointimal hyperplasia) to determine the functions of specific GRKs and beta-arrestins in atherosclerosis. In vivo progression of disease over time, as well as ex vivo neointimal lesion characterization in treated/untreated animals, will be studied.