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Regulation of APC-mediated PAR1 signaling

Institution: University of California, San Diego
Investigator(s): Michael Dores, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19FT-0157 Award: $135,000
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Smoking causes cardiovascular disease, a leading cause of death in the United States. More than 61 million Americans suffer from some form of cardiovascular disease, and health care costs for people with health problems related to smoking has risen to tens of billions of dollars according to health economists at the University of California. Smoking generates toxins that are absorbed into the bloodstream, directly contributing to the damage of endothelial cells, which are cells that line the blood vessel wall. Smoke-induced endothelial cell dysfunction is a contributory factor to many long-term effects on the cardiovascular system. Endothelial cell dysfunction promotes thrombosis (blood clots), the formation of which is a critical event in myocardial infarction (heart attacks) and stroke.

Thrombosis is initiated by a blood-borne protease known as thrombin. Thrombin formed during injury or inflammation acts locally and under nonpathological conditions thrombin activity is rapidly inhibited by the vascular endothelium. One molecule that regulates the generation of thrombin and protects against thrombosis is known as activated protein C (APC). APC also promotes cytoprotective signaling in endothelial cells through a poorly understood mechanism. Moreover, endothelial cell damage induced by smoking has been linked to decreased APC generation, which can contribute to thrombosis. Remarkably, thrombin and APC stimulate endothelial cellular responses through the same receptor, Protease-Activated Receptor 1 (PAR1). Precise regulation of PAR1 signaling is crucial for proper endothelial cell function. The focus of this proposal is to understand the molecular basis by which PAR1 signaling is regulated following activation by APC in human endothelial cells. This knowledge is critical for developing novel strategies and for identifying new targets that can be used in the prevention and treatment of vascular endothelial cell dysfunction, a pathological condition associated with smoking and a major cause of cardiovascular disease.

ALIX binds to a YPX3L motif of PAR1 and mediates ESCRT-III/MVB sorting_x000D_ independent of ubiquitination
Periodical: Journal of Cell Biology Index Medicus:
Authors: Dores MR, Chen B, Lin H, et al. ART
Yr: 2012 Vol: 197 Nbr: 3 Abs: Pg: 407-419

AP-3 regulates PAR1 ubiquitin-independent MVB/lysosomal sorting via an ALIX-mediated pathway
Periodical: Molecular Biology of the Cell Index Medicus:
Authors: Dores MR, Paing MM, Montagne WA, Lin H, Marchese A, Trejo J. ART
Yr: 2012 Vol: 23 Nbr: 18 Abs: Pg: 3612-3623