Abstract

The broad long term objectives of this proposal are to understand the interactions between the humoral clotting factors and components of the vessel wall including collagen IV, platelets, endothelium and the thrombin- thrombomodulin complex on endothelium. Recent evidence shows that collagen IV specifically binds factor IV, but the functional consequence of this interaction is unknown, but will be sought during this grant period. Furthermore, collagen IV is an agonist for alpha2beta1 on platelets and triggers an intracellular collagen receptor kinase, whose role in platelet physiology will be explored. The regulatory role of the protein C inhibitor on activated protein C resulting from the action of thrombin- thrombomodulin complex will also be sought. Finally, structure-function studies in factor IV and other clotting factors will be carried out. These studies will be carried out over the next five years and should gretly add to our understanding of the physiology of normal hemostasis as well as the pathological consequences of thrombosis and hemorrhage, both of which contribute to great mortality and morbidity in this country.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL006350-41
Application #
6490298
Study Section
Special Emphasis Panel (ZHL1-PPG-D (M1))
Program Officer
Link, Rebecca P
Project Start
1979-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
41
Fiscal Year
2002
Total Cost
$1,565,777
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

Bode, Michael F; Mackman, Nigel (2016) A combined deficiency of tissue factor and PAR-4 is associated with fatal pulmonary hemorrhage in mice. Thromb Res 146:46-50
Boulaftali, Yacine; Owens 3rd, A Phillip; Beale, Ashley et al. (2016) CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. Arterioscler Thromb Vasc Biol 36:792-9
Owens 3rd, A Phillip; Edwards, Todd L; Antoniak, Silvio et al. (2015) Platelet Inhibitors Reduce Rupture in a Mouse Model of Established Abdominal Aortic Aneurysm. Arterioscler Thromb Vasc Biol 35:2032-2041
Wu, Sangwook; Lee, Chang Jun; Pedersen, Lee G (2014) Analysis on long-range residue-residue communication using molecular dynamics. Proteins 82:2896-2901
Bode, Michael; Mackman, Nigel (2014) Regulation of tissue factor gene expression in monocytes and endothelial cells: Thromboxane A2 as a new player. Vascul Pharmacol 62:57-62
Wu, Sangwook; Beard, William A; Pedersen, Lee G et al. (2014) Structural comparison of DNA polymerase architecture suggests a nucleotide gateway to the polymerase active site. Chem Rev 114:2759-74
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2014) Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization. Adv Protein Chem Struct Biol 97:83-113
Parker, Christine H; Morgan, Christopher R; Rand, Kasper D et al. (2014) A conformational investigation of propeptide binding to the integral membrane protein ?-glutamyl carboxylase using nanodisc hydrogen exchange mass spectrometry. Biochemistry 53:1511-20
Boulaftali, Yacine; Hess, Paul R; Getz, Todd M et al. (2013) Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 123:908-16
Mutoh, Shingo; Sobhany, Mack; Moore, Rick et al. (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 6:ra31

Showing the most recent 10 out of 57 publications