Cardiovascular disease and stroke are major causes of morbidity and mortality. Although many pathophysiological processes play a role in the development of vascular disease, thrombosis often is the event that precipitates stroke and acute coronary syndromes. Many platelet receptors and activation pathways are conserved in other cell types, including neurons. Platelets release the neurotransmitter glutamate during activation, but the role of glutamate signaling in the vasculature is unknown. We have discovered that platelets express ionotropic glutamate receptors, including the AMPA type receptor (AMPAR) and the Kainic Acid (KA) type receptor (KAR). Furthermore, we demonstrate that AMPA and KA receptor signaling increase platelet activation. We hypothesize that platelets express functional glutamate sensitive complexes that increase agonist induced platelet activation and thrombosis. To explore this hypothesis, we propose the following Specific Aims:
Specific Aim 1 : To define the mechanisms of glutamate mediated increase in agonist induced platelet activation. We will extend our extensive Preliminary Data to further explore the regulation of platelet activation by ionotropic glutamate receptors. Using flow cytometry, platelet aggregation, and whole cell patch clamp techniques we will further dissect platelet glutamate signaling.
Specific Aim 2 : To define platelet glutamate receptor accessory molecule interactions.
Aim 2 will focus on the molecular machinery that facilitates AMPAR and KAR membrane localization and stability in platelets.
Specific Aim 3 : To demonstrate that glutamate signaling promotes thrombosis and ischemia-reperfusion injury. To further explore glutamate regulation of platelet function we will use in vivo measurements of platelet function, including bleeding time and thrombosis. We will also demonstrate the importance of the promotion of platelet activation by AMPAR and KAR using a model of ischemia- reperfusion injury.

Public Health Relevance

In 2001, a World Health Report noted atherothrombosis (ischemic heart disease and stroke) to be the leading cause of death worldwide. Platelets have a prominent role in cardiovascular disease and platelet inhibitors are a main therapeutic intervention. The proposed study will help elucidate novel targets for the development of new therapies in the prevention and treatment of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094547-04
Application #
8255473
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Kindzelski, Andrei L
Project Start
2009-08-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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