Platelet activation at sites of vascular injury lies at the core of the hemostatic mechanism and provides an important model for the study of signal transduction as well as a target for therapeutic intervention. The goal of proposed studies is to understand three aspects of platelet biology: 1) the mechanism by which human platelet activation is initially triggered through receptors on the cell surface, 2) the molecular interactions within the platelet that are necessary for propagating the signals that begin with the receptor activation, and 3) the role of cell surface molecules in generating further intracellular signaling once direct contact has been established between activated platelets, endothelial cells and leukocytes. In the first of the three proposed specific aims, we will continue our studies on the structure and function of the G protein-coupled receptors that are present in platelets, including, but not limited to, the protease-activated receptors. These studies will examine, among other things, the interaction of these receptors with protease in and around the vascular space and the organization of platelet agonist receptors into signaling complexes within the plane of the lipid bilayer. The second specific aim will focus on the signaling events downstream from G protein-coupled receptors in platelets, examining the pathways that ultimately lead to integrin activation and granule secretion, as well as the integration that occurs between signals separately generated from G protein-coupled receptors and integrins. The final specific aim will examine the hypothesis that contracts between platelets, leukocytes and endothelial cells (mediated in part by integrins and selectins) trigger events within the cells by the engagement of a recently-described family of cell surface tyrosine kinases (the Eph kinases) with their cognate cell surface ligands (the LERKs) on adjacent cells. Preliminary data that are included in this proposal show for the first time that these molecules are expressed in human platelets and leukocytes, and extend the repertoire of Eph kinases and LERKs that have previously been identified in endothelial cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Capitano, Maegan; Zhao, Liang; Cooper, Scott et al. (2018) Phosphatidylinositol transfer proteins regulate megakaryocyte TGF-?1 secretion and hematopoiesis in mice. Blood 132:1027-1038
Branchford, B R; Stalker, T J; Law, L et al. (2018) The small-molecule MERTK inhibitor UNC2025 decreases platelet activation and prevents thrombosis. J Thromb Haemost 16:352-363
Zhao, Baobing; Mei, Yang; Cao, Lan et al. (2018) Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms. J Clin Invest 128:125-140
Khandelwal, Sanjay; Ravi, Joann; Rauova, Lubica et al. (2018) Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood 132:2431-2440
Villa, Carlos H; Pan, Daniel C; Johnston, Ian H et al. (2018) Biocompatible coupling of therapeutic fusion proteins to human erythrocytes. Blood Adv 2:165-176
Ma, Peisong; Gupta, Shuchi; Sampietro, Sara et al. (2018) RGS10 shapes the hemostatic response to injury through its differential effects on intracellular signaling by platelet agonists. Blood Adv 2:2145-2155
Gupta, Shuchi; Cherpokova, Deya; Spindler, Markus et al. (2018) GPVI signaling is compromised in newly formed platelets after acute thrombocytopenia in mice. Blood 131:1106-1110
Xie, Zhigang; Hur, Seong Kwon; Zhao, Liang et al. (2018) A Golgi Lipid Signaling Pathway Controls Apical Golgi Distribution and Cell Polarity during Neurogenesis. Dev Cell 44:725-740.e4
Greineder, Colin F; Johnston, Ian H; Villa, Carlos H et al. (2017) ICAM-1-targeted thrombomodulin mitigates tissue factor-driven inflammatory thrombosis in a human endothelialized microfluidic model. Blood Adv 1:1452-1465
Welsh, J D; Poventud-Fuentes, I; Sampietro, S et al. (2017) Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature. J Thromb Haemost 15:526-537

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