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 #
5R01HL094547-03
Application #
8067125
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
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$385,625
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Shi, Guanfang; Field, David J; Long, Xiaochun et al. (2013) Platelet factor 4 mediates vascular smooth muscle cell injury responses. Blood 121:4417-27
Heo, Kyung-Sun; Chang, Eugene; Takei, Yuichiro et al. (2013) Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33:321-9
Aggrey, Angela A; Srivastava, Kalyan; Ture, Sara et al. (2013) Platelet induction of the acute-phase response is protective in murine experimental cerebral malaria. J Immunol 190:4685-91
Kuo, Hsiao-Hsuan; Morrell, Craig N; Baldwin 3rd, William M (2012) Alloantibody induced platelet responses in transplants: potent mediators in small packages. Hum Immunol 73:1233-8
Chapman, Lesley M; Aggrey, Angela A; Field, David J et al. (2012) Platelets present antigen in the context of MHC class I. J Immunol 189:916-23
Shi, Guanfang; Morrell, Craig N (2011) Platelets as initiators and mediators of inflammation at the vessel wall. Thromb Res 127:387-90
Ramesh, Sangeetha; Morrell, Craig N; Tarango, Cristina et al. (2011) Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via *2GPI and apoER2. J Clin Invest 121:120-31
Davidson, Donna C; Hirschman, Michael P; Spinelli, Sherry L et al. (2011) Antiplatelet activity of valproic acid contributes to decreased soluble CD40 ligand production in HIV type 1-infected individuals. J Immunol 186:584-91
Morrell, Craig N; Maggirwar, Sanjay B (2011) Recently recognized platelet agonists. Curr Opin Hematol 18:309-14
Baldwin 3rd, William M; Kuo, Hsiao-Hsuan; Morrell, Craig N (2011) Platelets: versatile modifiers of innate and adaptive immune responses to transplants. Curr Opin Organ Transplant 16:41-6

Showing the most recent 10 out of 15 publications