Brian C. Cooley, PhD
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
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.
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
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, Nevado J, Mellad J, Yang D, St. Hilaire C, Negro A, Fang F, Chen G, San H, Walts AD, Schwartzbeck RL, Taylor B, Lanzer JD, Wragg A, Elagha A, Beltran LE, Berry C, Feil R, Virmani R, Ladich E, Kovacic JC, Boehm M: TGF-β signaling mediates endothelial to mesenchymal transition (EndMT) during vein graft remodeling. Science Translat Med 6:227ra34 [ePrint] PMID: 24622514
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 34:1636-1643, 2013 PMCID: PMC3675389
Shi G, Meister D, Daley RA, Cooley BC: Thrombodynamics of microvascular repairs: effects of antithrombotic therapy on platelets and fibrin. J Hand Surg [Am] 38:1784-1789, 2013
Sehgal A, Barros S, Ivanciu L, Cooley B, Qin J, Racie T, Hettinger J, Carioto M, Jiang Y, Brodsky J, Prabhala H, Zhang X, Attarwala H, Hutabarat R, Foster D, Milstein S, Charisse K, Kuchimanchi S, Maier MA, Nechev L, Kandasamy P, Kel'in AV, Nair JK, Rajeev KG, Manoharan M, Meyers R, Sorensen B, Simon AR, Dargaud Y, Negrier C, Camire RM, Akinc A. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Medicine 2015 [in press] Apr 13. doi: 10.1038/nm.3847
Cooley BC: Murine arterial thrombus induction mechanism influences subsequent thrombodynamics. Thromb Res [in press]
Lee N, Daley RA, Cooley BC: Rat posterior facial vein interpositional graft: a more relevant training model. Microsurgery 34:653–656, 2014.
Cooley BC: Experimental vein graft research: a critical appraisal of models. Heart Res Open J 2:53-59, 2015. http://dx.doi.org/10.17140/HROJ-2-110
Ellery PER, Maroney SA, Cooley BC, Luyendyk JP, Zogg M, Weiler H, Mast AE: A balance between TFPI and thrombin-mediated platelet activation is required for murine embryonic development. Blood 125:4078-84, 2015.