CELL ADHESION MECHANISMS IN VASCULAR DISEASE

  • Ginsberg, Mark Howard (PI)
  • Gardner, Humphrey A. (CoPI)
  • Loftus, Joseph C (CoPI)
  • Loskutoff, David J. (CoPI)
  • Ruggeri, Zaverio M. (CoPI)
  • Sarvetnick, Nora E. (CoPI)
  • Schwartz, Martin A. (CoPI)
  • Shattil, Sanford J. (CoPI)
  • Ginsberg, Mark H. (CoPI)

Project: Research project

Project Details

Description

Continued support is requested for a program designed to advanced understanding of molecular mechanisms of vascular disease and to promote development of new clinical strategies through the collaborative efforts of a group of experienced scientists focused on the unifying theme of cell adhesion. These studies will span analysis of fine structure at atomic level detail, biochemistry, somatic cell genetics, ex-vivo studies to analyze the effects of blood genetic predisposition to arterial thrombosis in human populations. Dr. Ginsberg will analyze cytoplasmic interaction of beta3, integrins through development, characterization and validation of novel mimics of the cytoplasmic domains of integrin alpha IIbbeta3 and alphavbeta3. The interaction between CD98 and integrin beta tails will be evaluated and related integrin function and amino acid transport. Additional beta3 integrin cytoplasmic domain binding proteins will be identified. Dr. Schwartz will analyze integrin-mediated activation of GTPases and other signaling events in endothelial cells subjected to shear stress and mechanical strain. The role of these mechanical event in activation of MAP kinases, oxidant production, regulation of NF-kappaB, and activation of the small GTPases, Rac, Rho, and Cdc42 will be assessed. Dr. Shattil will develop mouse megakaryocyte systems and methods by which various adhesive functions and signaling events can be readily assayed. Through genetic manipulation of these systems, studies previously conducted in model cell systems will be related to adhesive function in megakaryocytic environment. Dr. Ruggeri will evaluate the structural determinants of von Willebrand factor A1 domain function in both static and flowing conditions. Dr. Kunicki will characterize the relationship of defined alleles of integrin alpha1 to differences in expression of alpha2beta1 on platelets. He will assess the effect of variation in platelet alpha2beta1 expression in patients and genetically engineered mice or in flowing whole blood. Possible connections between alpha2 genotype and risk of bleeding or thrombosis in patients with coronary artery disease will be assessed. A transgenic mouse core will be used to engineer knockout mice for CD98 heavy chain and beta 3 endonexin. In addition this core will use the alpha2 knockout mice to generate mice with reduced platelet alpha2beta1 and will maintain stocks of vWF, TSP-2, integrin beta3, and integrin beta5 deficient mice. An administrative will continue to provide administrative support.
StatusFinished
Effective start/end date9/30/928/31/97

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