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Characterization of Platelet Thromboxane A2 Receptors

Institution: Western University of Health Sciences
Investigator(s): Fadi Khasawneh, PhD
Award Cycle: 2010 (Cycle 19) Grant #: 19KT-0030 Award: $277,422
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards

Initial Award Abstract
While cigarette smoking is the single most preventable risk factor for cardiovascular disease, a significant percentage of disabilities and deaths are attributable to it. In fact, cardiovascular disease such as the thrombosis-based disorders heart attacks and strokes are considered the main cause of death due to smoking. In this connection, thrombosis is defined as the formation of a blood clot inside a blood vessel, thereby obstructing blood flow to a particular organ or area of the body. To this end, smoking accelerates the hardening and narrowing process in blood vessels, which substantially contributes to the pathogenesis of certain cardiovascular disease such heart attacks. Importantly, it has been established that activation of blood cells known as platelets is an important risk factor in atherosclerosis caused by smoking.

In this connection, cigarette smoking was also found to stimulate the formation of a compound, thromboxane A2 (TXA2) that is known to activate platelets by binding to a protein (receptor) on their surface, and therefore contribute to thrombotic disorders. Interestingly, aspirin therapy was found to inhibit smoking-induced platelet activation; which makes it especially beneficial in decreasing cardiovascular mortality among smokers. Our goal is to investigate two aspects of the biology of the thromboxane A2 receptor protein using reagents (a novel inhibitor) that can be applied in the treatment of this tobacco-related disease. We will also study another protein that is found on the surface of platelets, called the transient receptor potential channel 6 (TRPC6), and its role in the function of platelets, which are also known to mediate some of the deleterious effects of tobacco use. The outcome of these studies may also result in a new ways for treating smoking induced platelet-dependent diseases.

In summary, our study focuses on a receptor protein that is known to mediate the adverse effects of smoking on blood cells called platelets. It may also result in the discovery of a novel therapeutic reagent or a new target for treating a common tobacco-related disease, such as heart attacks.

A Novel Antibody_x000D_ Targeting the Ligand Binding Domain of the Thromboxane A2 Receptor Exhibits Antithrombotic Properties in vivo
Periodical: Biochemistry and Biophysics Research Communications Index Medicus:
Authors: Murad J.P., Espinosa E.V.P., Ting H.J., McClure, D, and Khasawneh, F.T. ART
Yr: 2012 Vol: 421 Nbr: 3 Abs: Pg: 456-461

Mouse Transient Potential Channel 6: Role in Hemostasis and Thrombogenesis
Periodical: Biochemistry and Biophysics Research Communications Index Medicus:
Authors: Espinosa E.V.P., Murad J.P., Ting H.J., and Khasawneh, F.T. ART
Yr: 2012 Vol: 417 Nbr: 2 Abs: Pg: 853-856

The C-terminal Segment of the Second Extracellular Loop of the Thromboxane A2 Receptor Plays an Important Role in Platelet Aggregation
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Murad J.P., Ting H.J., Espinosa E.V.P., and Khasawneh, F.T. ART
Yr: 2012 Vol: 83 Nbr: Abs: Pg: 88-96