The central unifying theme of this competing renewal is the sub- endothelial extracellular matrix (ECM) and its role in thrombus formation and dissolution. The collaborative efforts of four senior scientists will focus on the influence of cell adhesion, integrins, flow forces, proteases and protease inhibitors on the assembly and structure of ECM. Dr. Loskutoff will study interactions between plasminogen activator inhibitor 1 (PAI-1), vitronectin (VN), and the urokinase receptor (uPAR). Their influence on ECM structure and function, on the adhesion, migration, and growth of cells in vitro, and on tumor cell-mediated angiogenesis in vivo, will be defined. The origin of platelet VN will be examined, and its contribution to the composition of ECM and thrombi will be studied using VM- and PAI-1-deficient mice. Dr. Ginsberg will study intracellular mechanisms that control integrin functions essential for the assembly insoluble fibronectin fibrils in ECM. He will employ noel genetic strategies and structural mimics to define the mechanisms responsible for """"""""activation"""""""" of the high affinity form of integrin alpha5beta1, and for its physical linkage to the cytoskeleton. Interactive sites in the integrin and the cytoskeletal proteins will be mapped, and the hypothesis that the differential binding of cytoskeletal proteins to integrins leads to integrin-specific functions will be tested. Dr. Ruggeri will study mechanisms responsible for platelet deposition at sites of vascular injury. He will define ECM components that influence platelet deposition at sites of vascular injury. He will define ECM components that influence platelet thrombus formation, characterize the thrombogenic properties of ECM proteins secreted by endothelial cells of different tissue origin and investigate the role of ECM in the bleeding defect in thrombospondin-2 deficient mice. The distinct roles of fibrinogen, fibronectin, vitronectin and integrin alphavbeta3 in platelet thrombus formation at normal and pathological shear rates will be assessed. Dr. Quigley will study mechanisms that initiate complex proteolytic enzyme cascades involved in ECM remodeling. The initiation and control of the uPA/plasmin cascade by a novel auto-activation step, by changes in intrinsic activity, and by PAI-1 and PAI-2 will be examined, and the link between this cascade and activation of select matrix metalloprotease cascades (MMP-3, MMP-9) will be investigated. Biochemical, cell biological and in vivo approaches using uPA-deficient and MMP-3- deficient mice will be employed. The work on the uPA/plasmin cascade is currently funded by NIH and will be folded into Project 4. The cores will be used by each of the projects to provide administrative activities and specialized monoclonal antibodies and to guarantee access to technically difficult in vitro and in vivo models of thrombus formation and dissolution.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL031950-20
Application #
6697533
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1984-04-01
Project End
2005-08-31
Budget Start
2004-01-01
Budget End
2005-08-31
Support Year
20
Fiscal Year
2004
Total Cost
$2,262,837
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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

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