Coronary heart disease (CHD) is the most common killer in both whites and blacks. However, blacks have a 2- fold increase in the incidence of CHD as well as a lower long-term survival compared to whites. These differences cannot be fully explained by demographic, clinical, or economic confounders between these groups. As myocardial infarction and stroke typically result from an occlusive platelet thrombus formed at the site of a ruptured atherosclerotic plaque, understanding differences in the mechanisms by which platelets are activated in blacks and whites is expected to aid in our ability to optimally treat these populations following myocardial infarction (MI) and stroke. Our preliminary data demonstrates, for the first time, 1) racial differences in PAR4-mediated platelet aggregation, and 2) platelet mRNAs and microRNAs that are differentially expressed (DE) between blacks and whites and regulate PRA4 activation. The goals of this application are to characterize 1) the critical pathways and proteins responsible for these racial differences in platelet function, and 2 the molecular genetic basis for differences in gene expression. These goals will be addressed with physiology, biochemistry, genomic and cell biology approaches in human platelets and megakaryocytes.
Aim 1 will dissect racial differences in platelet function using physiological and biochemical endpoints to assess PAR4 activation kinetics and absolute level of activity. By integrating the information attained in Aim 1, Aim 2 will evaluate novel candidate platelet genes DE expressed between blacks and whites. These genes will be characterized for their potential role in regulating the racial difference in PAR4-mediated reactivity of platelets. In particular, w find phosphatidylcholine transfer protein (PC-TP), is significantly higher in platelets from blacks compared to platelets from whites. PC-TP regulates lipid movement in the cell, a critical process in platelet activation. Several other strong candidate platelet genes - also DE by race - will also be characterized.
Aim 3 will focus on novel mechanisms of gene expression that account for racial differences in platelet aggregation. We have identified the first example of miRNAs that are DE by race and by PAR4-mediated platelet aggregation. We will genetically manipulate candidate miRNAs in cultured human megakaryocytes to assess their effects on regulating PAR4-mediated platelet/megakaryocyte reactivity. We will also assess the molecular basis for the differential expression of miRNAs. This study will be the first to characterize racial differences in platelet activation at the signaling, protein and genetic levels. Understanding the racial difference in platelet activity will fill a significant gap in our understanding of why blacs suffer a higher morbidity and mortality than whites following MI and stroke.

Public Health Relevance

Racial disparity between blacks and whites in the incidence of coronary heart disease (CHD) and subsequent survival after CHD events continues to be a major clinical problem. We have new data demonstrating platelets from blacks are more reactive than platelets from whites - a finding that could substantively contribute to enhanced thrombosis in coronary arteries in blacks, leading to a higher risk of myocardial infarction (and stroke). Identifying the molecular mechanisms driving this racial disparity is essential to provide the optimal and personalized management for each racial group that would most enhance treatment benefit and reduce treatment side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Project (R01)
Project #
5R01MD007880-02
Application #
8698813
Study Section
Special Emphasis Panel (ZMD1-MLS (02))
Program Officer
Rajapakse, Nishadi
Project Start
2013-07-09
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$348,750
Indirect Cost
$123,750
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Holinstat, Michael; Tourdot, Benjamin E (2015) Coronary heart disease risk factors take a disproportional toll on women. Arterioscler Thromb Vasc Biol 35:750-1
Buitrago, Lorena; Rendon, Augusto; Liang, Yupu et al. (2015) αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia. Proc Natl Acad Sci U S A 112:E1898-907
Holinstat, Michael; Reheman, Adili (2015) Dual antiplatelet therapy for PCI: Are we tailored to all? Thromb Res 135:1045-6
Londin, Eric; Loher, Phillipe; Telonis, Aristeidis G et al. (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci U S A 112:E1106-15
Qayyum, Rehan; Becker, Lewis C; Becker, Diane M et al. (2015) Genome-wide association study of platelet aggregation in African Americans. BMC Genet 16:58
Simon, Lukas M; Edelstein, Leonard C; Nagalla, Srikanth et al. (2014) Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood 123:e37-45
Tourdot, Benjamin E; Conaway, Stanley; Niisuke, Katrin et al. (2014) Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis. Arterioscler Thromb Vasc Biol 34:2644-50
Londin, Eric R; Hatzimichael, Eleftheria; Loher, Phillipe et al. (2014) The human platelet: strong transcriptome correlations among individuals associate weakly with the platelet proteome. Biol Direct 9:3
Luci, Diane K; Jameson 2nd, J Brian; Yasgar, Adam et al. (2014) Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase. J Med Chem 57:495-506
Edelstein, Leonard C; Simon, Lukas M; Lindsay, Cory R et al. (2014) Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood 124:3450-8

Showing the most recent 10 out of 14 publications