This competing revised application is for renewing P01-HL31950-26A1 (years 26-30). Three projects and two cores will combine efforts to advance understanding of the mechanisms underlying thrombosis and thrombotic diseases and new knowledge from this Program may define new therapeutic strategies for reducing disease burden. Project 1 (Griffin: Murine protein C and protein S proof of principle research) will focus on the initiation of signaling by activated protein C (APC) via apoER2 and Dabi in mice;on the structural elements of apoER2 that regulate its interactions with APC;and on a possible role for Dabi in APC-dependent mortality reduction in murine sepsis or antithrombotic activities in vivo. Novel APC mutants with selective loss of interaction with only one of its receptors (apoER2, PARI, or EPCR) or with the cofactor, protein S, will be engineered for evaluating consequences on inflammation and thrombosis, and the in vivo antithrombotic actions of protein S will be explored in murine thrombosis models. These highly synergistic aims will address critical knowledge gaps in the understanding of the mechanisms that initiate and regulate the response to vascular injury. Project 2 (Ginsberg: Adhesive signaling and vascular thromboresistance) will test the hypotheses that CD98 is important in the proliferation and function of cells in injured blood vessels, and that localized activation of Protein Kinase A in endothelial cells regulates cell alignment and migration through the phosphorylation of substrates, including integrin a4, and the resulting modification of Rho GTPase activities. Project 3 (Ruf: Regulation of tissue factor (TF) procoagulant properties in thrombosis) will test the hypotheses that TF procoagulant activity on cells is regulated by interactions with integrins and modulated by protease-activated receptor 2 (PAR2) signaling, and that the P2X7 receptor contributes to modulating TF activation releasing active TF-bearing micro particles from the vessel wall and into the intravascular compartment. Two Cores will provide support for all three Projects in terms of murine thrombosis in vivo model studies and administrative matters. New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis.

Public Health Relevance

Thrombosis and associated processes cause life-threatening damage to blood vessels and are associated with a large burden of morbidity and mortality. This Program proposes to continue basic multidisciplinary research on molecular and cellular mechanisms that regulate thrombosis and on potential life-saving therapies related to thrombotic and inflammatory disease processes. New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Link, Rebecca P
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Scripps Research Institute
La Jolla
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Griffin, John H; Mosnier, Laurent O; Fernández, José A et al. (2016) 2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C. Arterioscler Thromb Vasc Biol 36:2143-2151
Ruf, Wolfram; Rothmeier, Andrea S; Graf, Claudine (2016) Targeting clotting proteins in cancer therapy - progress and challenges. Thromb Res 140 Suppl 1:S1-7
Schmidt, Thomas; Ye, Feng; Situ, Alan J et al. (2016) A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors. J Biol Chem 291:17536-46
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Alsultan, Abdulrahman; Gale, Andrew J; Kurban, Kadijah et al. (2016) Activation-resistant homozygous protein C R229W mutation causing familial perinatal intracranial hemorrhage and delayed onset of thrombosis. Thromb Res 143:17-21
Abplanalp, Wesley T; Conklin, Daniel J; Cantor, Joseph M et al. (2016) Enhanced Integrin α4β1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes :
Wang, Yaoming; Zhao, Zhen; Rege, Sanket V et al. (2016) 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nat Med 22:1050-5
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