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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL031950-26A1
Application #
8151851
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1996-12-01
Project End
2016-05-31
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
26
Fiscal Year
2011
Total Cost
$1,651,339
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
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
Amar, Arun Paul; Sagare, Abhay P; Zhao, Zhen et al. (2017) Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. Neuropharmacology :
Klann, Jane E; Remedios, Kelly A; Kim, Stephanie H et al. (2017) Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool. J Immunol 198:4639-4651
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
Deguchi, Hiroshi; Navarro, Silvia; Payne, Amanda B et al. (2017) Low level of the plasma sphingolipid, glucosylceramide, is associated with thrombotic diseases. Res Pract Thromb Haemost 1:33-40
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
Ruf, Wolfram; Rothmeier, Andrea S; Graf, Claudine (2016) Targeting clotting proteins in cancer therapy - progress and challenges. Thromb Res 140 Suppl 1:S1-7
Bhat, Vikas; von Drygalski, Annette; Gale, Andrew J et al. (2016) Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa. Thromb Haemost 115:551-61
Abplanalp, Wesley T; Conklin, Daniel J; Cantor, Joseph M et al. (2016) Enhanced Integrin ?4?1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes 65:3505-3515

Showing the most recent 10 out of 422 publications