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Regulation of biased PAR1 signaling by ubiquitination

Institution: University of California, San Diego
Investigator(s): Joann Trejo, Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0083H Award: $279,941
Subject Area: General Biomedical Science
Award Type: Exploratory/Developmental Award
Abstracts

Initial Award Abstract
Smoking causes cardiovascular disease which is a leading cause of death in the United States with more than 61 million Americans suffering from some form of cardiovascular disease. The total costs for health care for people with health problems related to smoking is extraordinary in the tens of billions of dollars according to health economists at the University of California. Smoking generates toxins, which enter the blood stream and directly contribute to the development of cardiovascular disease. Toxins are generally thought to damage endothelial cells, which are cells that line the blood vessels. A substantial literature supports the notion that smoke-induced endothelial cell dysfunction is an early event that contributes to more long-term effects on the cardiovascular system. Endothelial cell dysfunction promotes thrombosis (blood clots), which is a critical event in myocardial infarction (heart attacks) and stroke.

The key initiator of thrombosis is a protease called thrombin. Thrombin activates endothelial cells, promotes inflammatory responses and disrupts endothelial cell barrier integrity, all of these events are hallmarks of endothelial cell dysfunction a pathological condition associated with smoking. However, in non-pathological conditions, the vascular endothelium performs critical functions important for shutting down thrombin activity and protecting against thrombosis. One molecule principally responsible for decreasing thrombin generation and promoting endothelial barrier protection is called activated protein C (APC). Remarkably, however, both thrombin and APC signal through the same cell surface receptor known as protease-activated receptor-1 (PAR1) to elicit opposing functions on endothelial barrier integrity. How two different proteins, thrombin and APC, act through the same receptor to cause opposite effects in endothelial cells is not known. The focus of this proposal is to understand at the molecular level how PAR1 can differentially regulate endothelial cellular responses. An understanding of the mechanisms by which thrombin and APC promote distinct endothelial cellular responses will enable us to develop new strategies to manipulate receptor signaling and will provide novel targets for the development of new drugs that can be use in the prevention and treatment of vascular endothelial cell dysfunction, a pathological condition induced by smoking.
Publications

Regulation of protease-activated receptor signaling by posttranslational modifications
Periodical: International Union of Biochemistry and Molecular Biology Life Index Medicus:
Authors: Grimsey N, Soto AG, Trejo J. ART
Yr: 2011 Vol: 63 Nbr: Abs: Pg: 403-411

Adaptor protein complex-2 (AP-2) and epsin-1 mediate protease-activated receptor-1 internalization via phosphorylation and ubiquitination-dependent sorting signals
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Chen B, Dores MR, Grimsey N, Canto I, Barker BL, Trejo J. ART
Yr: 2011 Vol: 286 Nbr: Abs: Pg: 40760-40770

Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through B-arrestin and dishevelled-2 scaffolds.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Soh UJK, Trejo J. ART
Yr: 2011 Vol: 108 Nbr: Abs: Pg: E1372-E1380

Allosteric modulation of protease-activated receptor signaling
Periodical: Mini Reviews in Medicinal Chemistry Index Medicus:
Authors: Canto I, Soh UJK, Trejo J. ART
Yr: 2012 Vol: 12 Nbr: Abs: Pg: 804-811