Abstract

The long term objective of this research is to understand the interactions between the glycosaminoglycan (GAG)-dependent serine proteinase inhibitor, heparin cofactor II (HCII), GAGs and thrombin and attempt to define how these interactions regulate the cytokine-like effects of thrombin. The first part of the proposal examines the structural features of HCII which specify its functional properties with respect to GAG and thrombin recognition. Proposed hypotheses will be tested by site-directed mutagenesis of recombinant HCII expressed in baculovirus-infected insect cells. The second part of the proposal aims to characterize and identify stromal elements from fibroblasts, smooth muscle cells and their extracellular matrix which accelerate the HCII-thrombin reaction and their modulation by inflammatory cytokines. The final part of the proposal focuses on defining the in vivo extravascular distribution of HCII, ATIII, HCII-binding proteoglycans and thrombin. The outcome of these experiments will provide a clearer understanding of the significance of HCII, thrombin and GAG interactions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032656-13
Application #
6030514
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2001-06-30
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Rau, Jill C; Mitchell, Jennifer W; Fortenberry, Yolanda M et al. (2011) Heparin cofactor II: discovery, properties, and role in controlling vascular homeostasis. Semin Thromb Hemost 37:339-48
Gramling, Mark W; Beaulieu, Lea M; Church, Frank C (2010) Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction. Exp Cell Res 316:314-28
Rau, Jill C; Deans, Carolyn; Hoffman, Maureane R et al. (2009) Heparin cofactor II in atherosclerotic lesions from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Exp Mol Pathol 87:178-83
Gonzales, Patrick R; Walston, Timothy D; Camacho, Laureano O et al. (2007) Mutation of the H-helix in antithrombin decreases heparin stimulation of protease inhibition. Biochim Biophys Acta 1774:1431-7
Rau, J C; Beaulieu, L M; Huntington, J A et al. (2007) Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 5 Suppl 1:102-15
Fortenberry, Y M; Whinna, H C; Cooper, S T et al. (2007) Essential thrombin residues for inhibition by protein C inhibitor with the cofactors heparin and thrombomodulin. J Thromb Haemost 5:1486-92
Beaulieu, Lea M; Church, Frank C (2007) Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res 313:677-87
Whitley, Brandi R; Beaulieu, Lea M; Carter, Jennifer C et al. (2007) Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells. Gynecol Oncol 104:470-9
Beaulieu, L M; Church, F C (2006) Is protein C inhibitor antithrombotic and protective in pulmonary hypertension? J Thromb Haemost 4:2327-30
Rehault, Sophie M; Zechmeister-Machhart, Margareta; Fortenberry, Yolanda M et al. (2005) Characterization of recombinant human protein C inhibitor expressed in Escherichia coli. Biochim Biophys Acta 1748:57-65

Showing the most recent 10 out of 72 publications