Role of thrombomodulin in the vascular response to injury
Thrombin at the site of vascular injury is a major effector of thrombosis, inflammation, and pathologic SMC physiology. Its endogenous inhibitor, thrombomodulin (TM) is a major focus of both in vitro and in vivo experimentation in the research laboratory. We have shown that intravenous administration of TM inhibits the arterial intimal hyperplastic reaction following balloon injury in a rabbit model. We are now working to explain this pathophysiologic observation with in depth study at the bench dissecting the physiology and biochemistry surrounding TM at the site of injury. We have shown TM to inhibit both thrombin-induced SMC proliferation and migration, and that TM, independent of thrombin, may have important direct controlling effects on SMC behavior affecting signaling from other growth factors such as PDGF.
Finally, TM appears to have a multidimensional effect by also displaying anti-inflammatory properties, the mechanisms of which will be examined. With SMC in culture, we are currently expanding our study of these underlying cellular signaling mechanisms with plans to repeat these analyses in SMC-EC co-culture models to more closely mimic the in vivo biology. Eventually, a variety of specific animal models will be reestablished to refine methods of TM delivery to sites of vessel injury. This work may involve creating constructs for transfection of SMC both in vitro and in vivo, protein engineering to create a TM with a transduction domain for direct cellular uptake, and the incorporation of TM into biomaterial strategies such as elution balloons, prosthetic graft materials, and drug-eluting stents.
We have an extensive clinical research effort underway on an ongoing basis. All residents are required to have at least one research project aiming at peer-reviewed publication ongoing at all times, and are strongly encouraged to submit at least one meeting abstract each year; we also have numerous opportunities to write chapters and invited reviews. We share access to an electronic “whiteboard” listing our research in progress which is reviewed as a group monthly; resources include PhD mathematical modelers, engineering students, a full-time database manager, and a research coordinator specifically devoted to the IRB approval process. Our residents typically graduate with between 5 and 15 manuscripts and 5 to 10 podium presentations to their credit. In the past three years 4 of our 6 graduates have pursued academic careers.