The foremost cause of death in humans is cardiovascular diseases such as myocardial infarction and stroke. Circulating platelets play an important role in the pathogenesis of these diseases. Platelets are anucleated cells with a complex cytoskeletal system, unique receptors, and specialized secretary granules. They are found in the circulation in high abundance, and respond to blood vessel injury by changing shape, secreting granular contents, and aggregation. This is advantageous in the regulation of physiological hemostasis, but can be unfavorable in pathological thrombosis. For this reason, understanding the mechanisms surrounding platelet aggregation is essential. Platelet function is tightly regulated by both pro- and anti-stimulatory mechanisms. Platelets are kept in an unstimulated state by little-known anti-stimulatory mechanisms. During vascular injury, pro-stimulatory mechanisms, such as signaling by various physiological agonists, override the anti-stimulatory machinery to achieve platelet aggregation. We have identified a novel platelet protein, ASK1, which appears to be a key participant in the pro-stimulatory mechanism. We hypothesize that ASK1 senses stress and/or pro-stimulatory signals initiated by agonists and transmits signals to the platelet fibrinogen receptor complex and helps in coordinating stimulatory signals that regulate platelet aggregation and thrombus formation. This proposal is focused on understanding the molecular mechanisms that are regulated by ASK1 in order to regulate platelet activation. The identification and characterization of such regulatory mechanisms may define new targets for developing potential therapeutic agents toward thrombotic disorders.

Public Health Relevance

Regulation of platelet aggregation is paramount in achieving hemostasis and controlling thrombosis. Unwanted diversion from this regulation may result in life-threatening pathological conditions such as myocardial infarction and stroke. Full understanding of these processes and identification of novel intermediate signaling events/players may help in developing new therapeutic strategies to overcome these pathological conditions. The proposed research has potential to identify such targets that regulates platelet functions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113188-02
Application #
8605910
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Kindzelski, Andrei L
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$344,250
Indirect Cost
$119,250
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716