The overall, long-term objective of this project is to achieve further understanding of the mechanisms underlying growth regulation in the vascular wall. Injury and disease of the vascular wall is characterized, in large part, by proliferation of vascular smooth muscle (VSMC), leading to occlusion of the vessel lumen. Exogenous heparin and endogenous heparin sulfates inhibit VSMC proliferation seen following surgical procedures, e.g., bypasses, endarterectomies, heart transplantation, and vein grafts, and the latter suggesting a regulatory role for heparan sulfates in vascular growth control.
The specific aims of this project are twofold: firstly, to uncover the cellular and molecular mechanisms whereby heparin and its derivatives inhibit VSMC growth. To these ends, heparin's effects on the early events in the activation of VSMC by mitogens will be studied. These include effects of heparin on the binding of specific mitogens to their receptors, receptor phosphorylations, phosphorylation of tyrosine residues in proteins, expression and/or phosphorylation of specific mitogen-dependent proteins, activation of protein kinase C, phosphatidylinositol metabolism, activation of the Na+/H+ antiport, intracellular pH changes, and cell-cycle proto-oncogene expression effects will be studied at the transcription and post-transcriptional levels. The relationship of the gene effects to inhibition of growth will be evaluated. Late events such as effects of VSMC adhesion, the relationship of adhesion to cell division, and isolation and characterization of the adhesion molecules involved, will be studied. Secondly, the effects of heparin and heparin derivatives, particularly nonanticoagulant, antiproliferative derivatives will be evaluated in regard to accelerated atherosclerosis observed in a rat heart transplant model, and in experimental vein grafts. In both these frequently performed procedures, VSMC proliferation is a major clinical problem.

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 #
5R37HL017747-18
Application #
3485538
Study Section
Pathology A Study Section (PTHA)
Project Start
1979-06-01
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
18
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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Shin, Y T; Adams, D H; Wyner, L R et al. (1995) Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model. Transplantation 59:1647-53

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