Angiogenesis during development, during healing and during tumor vascularization are processes which have major impact upon both an organism's ability to develop and survive. The control/modulation of angiogenesis is thought to involve integrated dynamic interactions among endothelial cells, extracellular matrix, soluble factors and other adjacent cell types. Advances in our understanding of these interactions in angiogenesis in the last several years have occurred in the areas of cell-cell, cell- matrix and cell-growth factor interactions. Cell-cell interactions between and among endothelial cells and endothelial cell-matrix interactions have been implicated in the various stages of the angiogenic process, including tube formation, maintenance and involution. Extracellular matrix-driven, integrin-mediated modulation of endothelial behavior has been shown to be critical in the angiogenic process. In particular, integrin modulation of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) phosphorylation has been shown to be an important regulator of angiogenesis both in vivo and in vitro. In particular, extracellular matrix-driven, integrin-mediated PECAM-1 tyrosine phosphorylation/dephosphorylation has been implicated in modulating endothelial cell migration, vasculogenesis and angiogenesis. Thus, the application proposes to elucidate the tyrosine and serine phosphorylation states of PECAM-1 and their effects on the conformation of the PECAM-1 ITAM domain, binding sites, and affinities for selected signalling and adapter molecules (c-src, SHPTP-2 and beta-catenin) and putative PECAM-1 - PECAM-1 interactions.
Each aim i s likely to provide novel information concerning PECAM-1. A particularly important aspect of this work is the use of 3D matrices to study endothelial biology. The investigator has been a leading figure in the use of the matrices. The environment is excellent for carrying out this work.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL028373-25
Application #
7027113
Study Section
Special Emphasis Panel (NSS)
Program Officer
Goldman, Stephen
Project Start
1990-02-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
25
Fiscal Year
2006
Total Cost
$549,608
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Flynn, Kelly M; Michaud, Michael; Canosa, Sandra et al. (2013) CD44 regulates vascular endothelial barrier integrity via a PECAM-1 dependent mechanism. Angiogenesis 16:689-705
Flynn, Kelly M; Michaud, Michael; Madri, Joseph A (2013) CD44 deficiency contributes to enhanced experimental autoimmune encephalomyelitis: a role in immune cells and vascular cells of the blood-brain barrier. Am J Pathol 182:1322-36
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Kim, Ji Il; Cordova, Alfredo C; Hirayama, Yo et al. (2008) Differential effects of shear stress and cyclic strain on Sp1 phosphorylation by protein kinase Czeta modulates membrane type 1-matrix metalloproteinase in endothelial cells. Endothelium 15:33-42

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