Brian C. Cooley, PhD
Faculty Director, Rodent Advanced Surgical Models Core Lab
Office: 3312B Molecular Biology Research Building
My main areas of interest are in two areas: thrombosis and vein graft complications. In the field of thrombosis and hemostasis, I have developed novel models for inducing thrombosis and for intravital fluorescence imaging of thrombus development. Recent applications of these models and evaluative measures have explored the roles of a number of thrombosis-associated factors in augmenting or inhibiting clot formation: tissue factor pathway inhibitor, polyphosphate, surface-exposed collagen, elevated prothrombin, and several standard and new anti-platelet agents and anticoagulants. Continuing studies are exploring related thrombus-modulating factors and novel approaches to preventing thrombosis.
A major complication of bypass vein grafting is the development of neointimal thickening and inward remodeling of the graft, leading to vein graft stenosis. The sources of cells within the neointimal layer as well as the causative factor(s) for neointimal development are still not well characterized. A recent novel finding is that vein endothelial cells can undergo transdifferentiation into a smooth muscle phenotype within the developing neointima upon grafting into an arterial environment. This endothelial-mesenchymal transdifferentiation process is mediated by TGF-beta, following a Smad2/3-Slug cell signaling pathway. Future studies will be directed at dissecting this TGF-mediated process, with a goal of determining new therapeutic approaches for inhibiting vein graft stenosis.
|Intravital fluorescence imaging of mouse carotid artery with electrolytic injury applied for 30 seconds to a 150-micron region on the outer surface. The video shows a time-lapse development of subsequent thrombus growth, embolization, and regrowth (flow from left to right), over 60 minutes (1 second of playing time equals 2 minutes of thrombogenesis time). Platelets are shown in red; fibrin (anti-fibrin) is shown in green. Bar = 300 microns (vessel diameter ~400 microns).
(from Cooley BC: In vivo fluorescence imaging of large-vessel thrombosis in mice. Arterioscler Thromb Vasc Biol 31:1351-1356, 2011. PMCID: PMC3098306)
Cooley BC, Ma L, Gould JS: Rat femoral vein-to-vein grafts as a microvascular practice model: Factors that influence patency. Microsurgery 12:43-45, 1991.
Cooley BC, Li XL, Dzwierzynski W, Gruel SM, Wright RR, Hall R, O'Brien EM, Fagan D, Hanel DP, Gould JS: The de-endothelialized rat carotid arterial graft: A versatile experimental model for the investigation of arterial thrombosis. Thrombosis Research 67:1-14, 1992
Ozbek MR, Brown DM, Deune EG, Lantieri LA, Kania NM, Pasia EN, Cooley BC, Wun T-C, Khouri RK: Topical tissue factor pathway inhibitor improves free-flap survival in a model simulating free-flap errors. J Reconstr Microsurg 11:185-188, 1995.
Cooley BC: Heat-induced tissue fusion in microvascular anastomosis. Microsurgery 17:198-208, 1996.
Cooley BC, Daley RA: Free flap transplantation in mice. Microsurgery 18:320-323, 1998.
Cooley BC, Daley RA: Murine microvascular anastomosis model of thrombosis. Thrombosis Res 96:157-159, 1999.
Khouri RK, Sherman R, Buncke HJ, Axel-Feller M, Hovius S, Benes CO, Ingram DM, Natarajan NN, Sherman JW, Yeramian PD, Cooley BC: A Phase II trial of intraluminal irrigation with recombinant human tissue factor pathway inhibitor to prevent thrombosis in free flap surgery. Plast Reconstr Surg 107:408-415, 2001.
Cooley BC: Murine model of neointimal formation and stenosis in vein grafts. Arterioscler Thromb Vasc Biol 24: 1180-1185, 2004.
Cooley BC, Chen C-Y, Friedman K, Datta YH: A prothrombotic phenotype in the Copenhagen rat strain. Thrombosis Res 115:153-157, 2005.
Cooley BC: A model of murine interpositional vein grafting. Microsurgery 25:209-212, 2005.
Cooley BC, Daley RA, Toth JM: Long-term BMP-2 induced bone formation in rat island and free flaps. Microsurgery 25:167-173, 2005.
Cooley BC, Szema L, Chen CY, Schwab JP, Schmeling G: A murine model of deep vein thrombosis: characterization and validation in transgenic mice. Thrombosis and Haemostasis 94:498-503, 2005.
Rao R, Bagaria V, Cooley BC: Posterolateral intertransverse lumbar fusion in a mouse model: surgical anatomy and operative technique. The Spine Journal 7:61-67, 2007.
Cooley BC, Chen CY, Schmeling G: Increased venous versus arterial thrombosis in the Factor V Leiden mouse. Thrombosis Res 119:747-751, 2007
Kusada A, Isogai N, Cooley BC: Electric injury model of murine arterial thrombosis. Thrombosis Res 121:103-106, 2007.
Cooley BC: Differential neointimal response in vein grafts and wire-injured arteries. Circ J 71:1649-1652, 2007.
Ionova IA, Vásquez-Vivar J, Whitsett J, Herrnreiter A, Medhora M, Cooley BC, Pieper GM: Deficient BH4 production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes. Am J Physiol Heart Circ Physiol 295:H2178-H2187, 2008. PMCID: PMC2614582
Rao R, Gourab K, Bagaria VB, Shidham VB, Metkar U, Cooley BC: The effect of platelet rich plasma and bone marrow on murine posterolateral lumbar spine arthrodesis with bone morphogenetic protein. J Bone Joint Surg [Am] 91:1199-1206, 2009.
Ionova IA, Vásquez-Vivar J, Cooley BC, Khanna AK, Whitsett J, Herrnreiter A, Migrino RQ, Ge J-D, Regner KR, Channon KM, Alp NJ, Pieper GM: Cardiac myocyte-specific over-expression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection. Am J Physiol - Heart Circ 299:H88-H96, 2010. PMCID: PMC2904123
Pieper GM, Shah A, Harmann L, Cooley BC, Ionova IA, Migrino RQ: Speckle-tracking 2-dimensional strain echocardiography: A new noninvasive imaging tool to evaluate acute rejection in cardiac transplantation. J Heart Lung Transplant 29:1039-1046, 2010. PMCID: PMC2926230
Cooley BC: In vivo fluorescence imaging of large-vessel thrombosis in mice. Arterioscler Thromb Vasc Biol 31:1351-1356, 2011. PMCID: PMC3098306
Cooley BC: Murine models of thrombosis. Thrombos Res 129 Suppl 2:S62-S64, 2012.
Yassai M, Cooley B, Gorski J: Developmental dynamics of post selection thymic iNKT. PLoS ONE 7:e43509, 2012. PMCID: PMC3425480
Cooley BC: Collagen-induced thrombosis in murine arteries and veins. Thrombos Res 131:49-54, 2013.
Cooley BC, Chen CY, Hess R, Schmeling G: Incomplete resolution of deep vein thrombosis under reduced flow conditions. Thrombos Res 131:55-58, 2013.
McDonald RA, White KM, Wu J, Cooley BC, Robertson KE, Halliday C, Lu R, Kennedy S, George SJ, Wan S, van Rooij E, Baker AH: MiRNA-21 is dysregulated in response to vein grafting in mulitple models and genetic ablation in mice attenuates neointima formation. Eur Heart J [in press]
Cooley BC, Herrera AJ: Cross-modulatory effects of clopidogrel and heparin on platelet and fibrin incorporation in thrombosis. Blood Coag Fibrinolysis [in press]
Aleman MM, Walton BL, Byrnes JR, Wang JG, Heisler MJ, Machlus KR, Cooley BC, Wolberg AS: Elevated prothrombin promotes venous, but not arterial, thromdbosis in mice. Arterioscler Thromb Vasc Biol [in press]
Shi G, Meister D, Daley RA, Cooley BC: Thrombodynamics of microvascular repairs: effects of antithrombotic therapy on platelets and fibrin. J Hand Surg [Am] [in press]