Long term objectives: The proposed studies, coupled with closely mentored laboratory guidance, seminars and course work will significantly broaden the applicant's scientific education and lead to an independent investigator status. Research: Unlike much arterial vascular disease, venous thrombotic disease lacks a consistently effective therapeutic approach outside of anticoagulation prophylaxis and treatment. Deep venous thrombosis resolution involves inflammatory mediator and cellular responses similar to the wound healing process. Chemokines are central to many inflammatory processes. The CXC subfamily are primary chemoattractants and activators of PMNs, and are directly proangiogenic. This proposal will utilize cell culture and two small animal models of DVT to answer the following specific aims: 1) To define the role of CXC chemokines and their effector leukocytes on molecular and cellular deep vein thrombosis resolution, 2) To determine the in vitro role of CXC chemokines on neutrophil derived fibrincilytic and angiogenic mediators, and 3) To determine the role of neutrophils and the effect of exogenous proangiogenic and angiostatic CXC chemokines on physiological deep vein thrombosis resolution. Molecular biological, immunological, as well as in vitro and in vivo angiogenesis bioassays, in conjunction with physiologic assays, will be used to achieve the above aims. Defining the basic chemokine mediated DVT resolution pathophysiology will potentially yield phamacologic or cellular based therapies to hasten DVT resolution for decreased peri-thrombotic inflammation, decreased vein wall damage, and decreased risk of pulmonary embolism.
| Dewyer, Nicholas A; Sood, Vikram; Lynch, Erin M et al. (2007) Plasmin inhibition increases MMP-9 activity and decreases vein wall stiffness during venous thrombosis resolution. J Surg Res 142:357-63 |
| Henke, Peter K; Varma, Manu R; Deatrick, K Barry et al. (2006) Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization. Thromb Haemost 95:272-81 |
| Varma, Manu R; Moaveni, Daria M; Dewyer, Nicholas A et al. (2004) Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 40:536-42 |
| Henke, Peter K; Varga, Andrea; De, Sumit et al. (2004) Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model. Arterioscler Thromb Vasc Biol 24:1130-7 |
| Varma, Manu R; Varga, Andrea J; Knipp, Brian S et al. (2003) Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 38:1090-8 |
