The transglutaminases (TGases) comprise a gene superfamily responsible for stabilizing both inter- and intra-molecular protein linkages through the formation of N-E-(y-glutamyl)lysine bonds. Members of the transglutaminase superfamily mediate essential biological functions including stabilization of the fibrin clot (factor XIII) and the epidermis (keratinocyte and epidermal TGs). The tissue transglutaminase (tTG) is a unique member of this family in that it both 1) stabilizes the extracellular matrix (ECM) and 2) functions as a G-protein coupled signaling molecule. The investigators hypothesize that tTG regulates the response to vascular injury by promoting assembly of the provisional fibrin matrix and regulating ECM formation and angiogenesis during the vascular repair process. In aim 1, the investigators will investigate how tTG functions to make fibrin resistant to fibrinolysis. In aim 2, they will study tTGs ability to modulate the stable attachment of endothelial cells. In aim 3, they will overexpress tTG and tTG mutants in cells to examine the effect on cell adhesion and protease resistance. And in aim 4 they will examine the role of tTG in fibrin-dependent angiogenesis in vivo.

The proposal comprises a 5-year plan designed to prepare the applicant for an independent research career related to perioperative hemostasis, thrombosis, and vascular medicine. In addition to the supervised laboratory research experience proposed, the applicant will complete selected graduate courses in protein and membrane structure and function, nucleic acids, and receptor signaling. The applicant will also participate in weekly seminars focusing on vascular biology and recent advances in molecular medicine. The training environment for this award will be Duke University Medical Center. The mentor for this training program will be Dr. Charles Greenberg, a recognized authority in the fields of fibrin stabilization and transglutaminase biology. Results from these investigations will provide new insights into the regulation of ECM assembly and vascular repair with implications for wound healing and the disease processes of atherosclerosis and thrombosis.

K08HL003205

1997-01-01

2001-12-31