Lisa K. Jennings, Ph.D., Professor, Department of Medicine
Director, Vascular Biology Center of Excellence

TM4SF proteins are implicated in a variety of normal and pathological processes that involve cell adhesion, motility, proliferation and differentiation. For example, TM4SF proteins are associated with events such as wound repair, platelet activation, neurite outgrowth, egg-sperm fusion, tumor-cell metastasis and virus-induced syncytium formation. We have shown that expression of CD9, a TM4SF protein, has significant effects on Chinese Hamster Ovary (CHO) cell adhesion, spreading, pericellular fibronectin matrix assembly and haptotactic motility to the extracellular matrix protein fibronectin (FN), a protein critical in developing and maintaining cell-matrix integrity. Additionally, the revised proposal incorporates the use of the smooth muscle cell model system in conjunction with the CHO cell model system.

Recent data demonstrate that CD9 expression on smooth muscle cells facilitates cell motility in wound healing assays and inhibits smooth muscle cell proliferation. An in vivo model of vascular injury showed that CD9 blockade inhibited neointima formation up to 28 days post carotid ligation injury. These new findings support a connection between CD9 expression and response to vascular injury. With respect to the mechanisms that drive these functions, we have also shown that CD9 expression affects integrin b1 linkage to the cytoskeleton suggesting that CD9 expression influences the complexes that bind cells to FN. We have also demonstrated that CD9 expression significantly increases cell motility via PI 3-kinase and Src dependent pathways and that FAK and p130Cas phosphorylation states may be an integral link to the observed cell phenotypes.

Recent Publications

The pharmacodynamics of parenteral glycoprotein IIb-IIIa Inhibitors. Jennings LK, Jacoski MV and White MM. J Intervent Card 15(1):45-60, 2002.

Short term administration of bFGF enhances coronary collateral development without exacerbating atherosclerosis and balloon injury induced vasoproliferation in atherosclerotic rabbits with acute myocardial infarction. Zhang C, Yang J, Feng J and Jennings LK. J Lab Clin Med 140(2):119-125, 2002.

Longhurst CM, Jacobs J, White MM, Crossno JT Jr, Fitzgerald DW, Bao J, Fitzgerald T, Raghow R and Jennings LK. Chinese hamster ovary cell motility to fibronectin Is modulated by the second extracellular loop of CD9: Identification of a putative fibronectin binding site. J Biol Chem 277(36):32445-32452, 2002.

Haga JH, Slack SM and Jennings LK. Comparison of shear-stress-induced platelet microparticle formation and phosphatidylserine expression in the presence of aIIbb3 antagonists. J Cardiovas Pharm 41(3):363-71, 2003.

Haga JH, Jennings LK and Slack SM. Inhibition of shear-stress-induced platelet aggregation and phosphotyrosine signaling by GPIIb-IIIa antagonists. Ann Biomed Eng 30(10):1262-72, 2002.

Identification of CD9 extracellular domains important in regulation of CHO cell adhesion to fibronectin and fibronectin pericellular matrix assembly. Cook GA, Grgurevich S and Jennings LK. Blood 100(13):4502-4511, 2002.

Identification of CD9 extracellular domains important in regulation of CHO cell adhesion to fibronectin and fibronectin pericellular matrix assembly. Cook GA, Longhurst CM, Grgurevich S, Cholera S, Crossno JT Jr, Jennings LK. Blood 100(13):4502-11, 2002.

Thiol alkylation inhibits the mitogenic effects of platelet-derived growth factor and renders it proapototic via activation of STATS and p53 and induction of expression of caspase 1 and p21 waf1/cip1. Bhanoori M, Yellatura CR, Ghosh, SK, Hassid AV, Jennings, Lk and Rao GN. Oncogene 22(1):117-30, 2003.

Role of in-vitro cholesterol depletion in mediating human platelet aggregation. Grgurevich S. and Jennings, L.K. Thrombosis and Haemostasis 1:576-586, 2003.

Interaction of myeloperoxidase with vascular NAD(P)H oxidase-derived reactive oxygen species in vasculature: implications for vascular diseases. Zhang C, Yang J, Jacobs J and Jennings LK. Am J Physiol Heart Circ Physiol 285:h1-h10, 2003.

Leukocyte-derived myeloperoxidase amplifies high glucose-induced vascular dysfunction through the interaction with high glucose stimulated, vascular nonleukocyte-derived reactive oxygen species. Zhang C, Yang J, Jennings LK.Diabetes 53(11):2950-9. 2004.

Comparative pharmacodynamic evaluation of eptifibatide and tirofiban HCl In patients undergoing coronary Intervention-The TAM1 Study. Saucedo, J.F., Wolford, D.C., Cook, S.L., Ramanathan, K.B., Garza, L., Matin, Z., McGrew, F.A., Jacoski, M.V., Jennings, L.K. Am. J. Card., 93 (10) 1270-82, 2004.

Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery. Zhang, C., Yang, J., and Jennings, L.K. Am J Physiol. 287: H659-H666, 2004.

Association between platelet receptor occupancy after eptifibatide (Integrilin) therapy and patency, myocardial perfusion, and ST-segment resolution among patients with ST-segment resolution among patients with ST-segment elevation myocardial infarction. Gibson, C.M., Jennings, L.K., Murphy, S.A., Lorenz, D.P., Giugliano R.P., Harrington, R.A., Cholera, S., Krishnan, R., Califf, R.M., Braunwald, E.Circ. 110:679-84, 2004.

Comparative pharmacodynamic evaluation of eptifibatide and abciximab in patients with non-ST-segment elevation acute coronary syndromes: The TAM2 Study. Saucedo J.F., Lui H.K., Garza L., Guerra G.J., Jacoski, MV and Jennings, LK. J Thromb Thrombolysis, 18(2), 67-74, 2004.

Tetraspanin CD82 attenuates cellular morphogenesis through down-regulating integrin a6-mediated cell adhesion. He B., Liu L., Cook G.A., Grgurevich S., Jennings L.K. and Zhang X.A. J Biol Chem. 2005 Feb 4;280(5):3346-54.

The use of the point of care Helena ICHOR/Plateletworks® and the Accumetrics Ultegra® RPFA for assessment of platelet function with GPIIb-IIIa antagonists. White M.M., Krishnan R., Kueter T.J., Jacoski M.V., and Jennings L.K. J Thromb Thrombolysis, 18(3), 163-169, 2004.

The beta3 subunit of the integrin alphaIIbbeta3 regulates alphaIIb-mediated outside-in signaling. Liu J, Jackson CW, Gruppo RA, Jennings LK, Gartner TK. Blood. 2005 Jun 1;105(11):4345-52.

Rapamycin-coated expanded polytetrafluoroethylene bypass grafts exhibit decreased anastomotic neointimal hyperplasia in a porcine model. Cagiannos C, Abul-Khoudoud OR, DeRijk W, Shell DH 4th, Jennings LK, Tolley EA, Handorf CR, Fabian TC.J Vasc Surg. 2005 Nov;42(5):980-8.

TIMI Study Group. Comparison of Effects of Bare Metal Versus Drug-Eluting Stent Implantation on Biomarker Levels Following Percutaneous Coronary Intervention for Non-ST-Elevation Acute Coronary Syndrome. Gibson CM, Karmpaliotis D, Kosmidou I, Murphy SA, Kirtane AJ, Budiu D, Ray KK, Herrmann HC, Lakkis N, Kovach R, French W, Blankenship J, Lui HH, Palabrica T, Jennings LK, Cohen DJ, Morrow DA. Am J Cardiol. 2006 May 15;97(10):1473-1477.

L-arginine chlorination results in the formation of a nonselective nitric oxide synthase inhibitor. Yang J, Ji R, Cheng Y, Sun JZ, Jennings LK and Zhang C. J Pharmacol Exp Ther. 2006 May 22. [Epub ahead of print]

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