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)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Klann, Jane E; Kim, Stephanie H; Remedios, Kelly A et al. (2018) Integrin Activation Controls Regulatory T Cell-Mediated Peripheral Tolerance. J Immunol 200:4012-4023
Griffin, John H; Zlokovic, Berislav V; Mosnier, Laurent O (2018) Activated protein C, protease activated receptor 1, and neuroprotection. Blood 132:159-169
Sinha, Ranjeet K; Wang, Yaoming; Zhao, Zhen et al. (2018) PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 131:1163-1171
Xu, Xiaohong Ruby; Wang, Yiming; Adili, Reheman et al. (2018) Apolipoprotein A-IV binds ?IIb?3 integrin and inhibits thrombosis. Nat Commun 9:3608
Gupta, Naveen; Liu, Roland; Shin, Stephanie et al. (2018) SCH79797 improves outcomes in experimental bacterial pneumonia by boosting neutrophil killing and direct antibiotic activity. J Antimicrob Chemother 73:1586-1594
Gupta, Naveen; Sinha, Ranjeet; Krasnodembskaya, Anna et al. (2018) The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. Stem Cells 36:796-806
Amar, Arun Paul; Sagare, Abhay P; Zhao, Zhen et al. (2018) Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. Neuropharmacology 134:293-301
Kamikubo, Yuichi; Mendolicchio, G Loredana; Zampolli, Antonella et al. (2017) Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex. Blood 130:1661-1670
Rothmeier, Andrea S; Marchese, Patrizia; Langer, Florian et al. (2017) Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking. Arterioscler Thromb Vasc Biol 37:1323-1331
Subramaniam, Saravanan; Jurk, Kerstin; Hobohm, Lukas et al. (2017) Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood 129:2291-2302

Showing the most recent 10 out of 428 publications