The aim of this proposal is to elucidate the mechanism by which latent TGF-beta1 (LTGF-beta1) or a molecule very similar to LTGF-beta1 is activated in cocultures of endothelial cells (ECs) and smooth muscle cells (SMCs). We have established that endogenous LTGF-beta1 is activated by plasmin in specific heterotypic cocultures of bovine cells. We hypothesize that in these heterotypic cocultures, cell-cell contact induces changes in the PA-plasmin system which leads to the effective conversion of LTGF-beta1 into active TGF-beta1. This results in an inhibition of EC movement, mitosis, and perhaps, invasion. We hypothesize that upon heterotypic cell-cell contact, changes in the PA-plasmin system occur which lead to the availability of plasmin in a form which converts LTGF-beta1 to TGF-beta1. To test this hypothesis we shall (1) explore other combinations of cells to assess the generality of heterotypic cell-cell activation, (2) characterize changes in the PA-plasmin system which might lead to activation, and (3) characterize the role of gap junctions in this process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA023753-16
Application #
3166228
Study Section
Pathology B Study Section (PTHB)
Project Start
1978-02-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Mazzieri, R; Munger, J S; Rifkin, D B (2000) Measurement of active TGF-beta generated by cultured cells. Methods Mol Biol 142:13-27
Munger, J S; Harpel, J G; Giancotti, F G et al. (1998) Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1. Mol Biol Cell 9:2627-38