Support is requested for a new program in vascular biology and medicine with the goal of advancing the understanding of vascular disease and to promote the development of new diagnostic and therapeutic strategies. This will be achieved through the collaborative efforts of a group of experienced scientists focused on the unifying theme of cell adhesion. Dr. Ginsberg will study the mechanisms of affinity modulation of integrins by defining the structures in integrin cytoplasmic domains which control affinity state and cytoplasmic factors which interact with them. Integrins in a high affinity state will be expressed in vascular tissues in transgenic mice to examine potential pathologic roles and to develop new disease models. The predictive value of spontaneous platelet activation for negative outcomes in percutaneous transluminal angioplasty will be analyzed prospectively in patients with coronary artery disease, and the occurrence of spontaneous variants of alphaIIb which may lead to platelet activation in the circulation will be sought. Dr. Swartz will analyze signal transduction from integrins by defining structural and function requirements for regulation and transduction systems which control cell growth. As signalling mutants are identified, they will be expressed in specific tissues of transgenic mice to examine potential pathogenic properties and they will be localized in normal and pathological human vascular tissue. Dr. Plow will evaluate the molecular basis of ligand recognition by the leukocyte alphaM beta2 and alpha4 beta1 integrins which are involved in leukocyte localization in the vessel wall. These experiments, using protein-based, peptide, and recombinant DNA strategies, will define the structural basis of these interactions, and should provide novel tools to inhibit leukocyte localization. Dr. Ruggeri will dissect the GPIb binding site in von Willebrand factor by use of protein, peptide, immunochemical, and molecular biological approaches. Insights derived from this will be used to develop novel inhibitors of thrombosis which will be studied in ex vivo systems and in man. Dr. Loftus will utilize fundamental information concerning ligand binding domains of integrins to engineer novel gain or loss of function mutants. The capacity of these mutants, when expressed in lymphocytes of transgenic mice to induce immunosuppression will be assessed. Selected mutants will be transfected into endothelial cells as a potential means to enhance their seeding of vascular surfaces. A transgenic mouse core under the direction of Dr. Sarvetnick and an in situ hybridization and histology core under the direction of Drs. Loskutoff and Bernstein will facilitate the testing of in vitro hypotheses at the level of the whole animal, and in patients with cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048728-07
Application #
2771323
Study Section
Special Emphasis Panel (SRC (SI))
Program Officer
Davis, Jane R
Project Start
1992-09-30
Project End
1999-08-31
Budget Start
1998-09-18
Budget End
1999-08-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Cantor, Joseph M; Rose, David M; Slepak, Marina et al. (2015) Fine-tuning Tumor Immunity with Integrin Trans-regulation. Cancer Immunol Res 3:661-7
Estrach, Soline; Lee, Sin-Ae; Boulter, Etienne et al. (2014) CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction. Cancer Res 74:6878-89
Kim, Chungho; Ye, Feng; Ginsberg, Mark H (2011) Regulation of integrin activation. Annu Rev Cell Dev Biol 27:321-45
Tzima, Ellie; Schimmel, Paul (2006) Inhibition of tumor angiogenesis by a natural fragment of a tRNA synthetase. Trends Biochem Sci 31:7-10
Goto, Shinya; Tamura, Noriko; Ishida, Hideyuki et al. (2006) Dependence of platelet thrombus stability on sustained glycoprotein IIb/IIIa activation through adenosine 5'-diphosphate receptor stimulation and cyclic calcium signaling. J Am Coll Cardiol 47:155-62
Tzima, Eleni; Reader, John S; Irani-Tehrani, Mohamad et al. (2005) VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J Biol Chem 280:2405-8
Mazzucato, Mario; Cozzi, Maria Rita; Pradella, Paola et al. (2004) Distinct roles of ADP receptors in von Willebrand factor-mediated platelet signaling and activation under high flow. Blood 104:3221-7
Baglia, Frank A; Shrimpton, Corie N; Emsley, Jonas et al. (2004) Factor XI interacts with the leucine-rich repeats of glycoprotein Ibalpha on the activated platelet. J Biol Chem 279:49323-9
Kloeker, Susanne; Major, Michael B; Calderwood, David A et al. (2004) The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrin-mediated adhesion. J Biol Chem 279:6824-33
Kasirer-Friede, Ana; Cozzi, Maria Rita; Mazzucato, Mario et al. (2004) Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors. Blood 103:3403-11

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