This proposal is focused on the study of two key changes involved in the seeding of fibrin thrombi on the vessel wall a process contributing to an estimated 5 million episodes of venous thrombosis and 1.5 million cases of acute coronary thrombosis per year in the United States. One is the mechanism causing exposure of the binding sites (receptors) for fibrinogen and fibrin monomer on the luminal membrane of the endothelial cells, initiating clinically silent or apparent thrombosis. The second is derangement of the vitronectin receptor on the abluminal membrane of the endothelial cells causing their detachment and exposure of the thrombogenic subendothelial matrix. We will examine a spectrum of conditions which can trigger exposure of fibrinogen receptors on the luminal membrane of the endothelial cells including thrombin, hypoxia-oxidant shift, cytokines, and infection with Herpes viruses. The role of signal transducing mechanisms in regulating exposure of the fibrinogen receptor will be examined. The endothelial fibrinogen receptor on the luminal membrane will be isolated and characterized. We will search for the domain(s) of fibrinogen and fibrin monomer responsible for recognition of the fibrinogen receptor on endothelial cells and compare them with the domain recognizing the vitronectin receptor. To this end, development of specific inhibitors of the fibrinogen receptor on endothelial cells, while sparing the vitronectin receptor, will provide a novel approach to the prevention of venous thrombosis. The second major trust of this proposal is to study the regulation of the vitronectin receptor on the abluminal membrane of the endothelial cells responsible for maintaining the intactness of the endothelial carpet in the vessel wall. We will examine how signals generated on the luminal membrane of the endothelial cells are transduced to evoke changes in the vitronectin receptor on the abluminal surface. This will be extended to expression and function of the vitronectin receptor including Herpes virus- infected endothelial cells. We will examine a panel of synthetic peptide analogs of receptor recognition domains on adhesive proteins for their reactivity toward the vitronectin receptor to determine whether they are harmful or neutral toward endothelial cells. Thus, our research should add new understanding of basic mechanisms of endothelial injury and pave the way for development of protective measures (cytoprotection) to avert the initiation of fibrin seeding on the endothelial cells and their desquamation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030648-09
Application #
3341664
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-01-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212