Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE RANSOHOFFLABORATORYThe Department of NeurosciencesASSISTANT STAFFJavier Provencio, M.D.PROJECT STAFFSandhya Rani, Ph.D.RESEARCH ASSOCIATEDeRen Huang, M.D., Ph.D.POSTDOCTORAL FELLOWSMelissa Callahan, Ph.D.Astrid Cardona, Ph.D.Pia Kivisakk, M.D., Ph.D.Don Mahad, M.D.Richard M. Ransohoff, M.D.TECHNICAL ASSOCIATESTao He, M.S.Zaachary LeibsonMeggan SasseBarbara Tucky, B.S.Tao Wei, M.D.COLLABORATORSElizabeth Fisher, Ph.D. 1Andrzej R. Glabinski, Ph.D. 2Hans Lassmann, M.D. 3Claudia F. Lucchinetti, M.D. 4Robert H. Miller, Ph.D. 5Richard A. Rudick, M.D. 6George R. Stark, Ph.D. 7Bruce D. Trapp, Ph.D. 71Dept. of Biomed. Engineering,CCF2Medical Univ. of Lodz, Poland3Univ. of Vienna, Austria4Mayo Clinic, Rochester, MN5Case Western ReserveUniv.Sch. of Med., Cleveland, OH6Div. of Clin. Res.; Mellen Ctr.for Multiple Sclerosis, CCF7Dept. of Molecular Biology,CCF8Dept. of Neurosciences, CCFChemokines, Chemokine Receptors andPhysiology of the Nervous SystemChemokines are small peptides that governleukocyte trafficking and activation. Thereis a substantial and growing literatureconcerning their biological function in development,inflammation and degeneration of thenervous system.The core hypothesis of our research is thatchemokines and their receptors are significantlyinvolved in leukocyte invasion, differentiation,activation, tissue destruction and repair in theCNS. Furthermore, resident neural cells respondto locally produced chemokines both duringdevelopment and disease.To address this hypothesis and identifymolecular targets for therapy, we examinechemokine production and function. Thesestudies comprise tissue culture systems, diseasemodels and material from patients with neurologicaldisease. We make extensive use of transgenicand knockout mice to clarify how chemokinesexert remarkably specific effects in vivo, in the faceof apparent functional redundancy in vitro.Tsai, H.H., Frost, E., To, V., Robinson, S., Ffrench-Constant, C., Geertman, R., Ransohoff, R.M., and R.H. Miller(2002) The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cordby arresting their migration. Cell 110:373-383.Kieseier, B.C., Tani, M., Mahad, D., Oka, N., Ho, T., Woodroofe, N., Griffin, J.W., Toyka, K.V., Ransohoff, R.M.,and H.P. Hartung (2002) Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a centralrole for IP-10. Brain 125:823-834.Ransohoff, R.M., Wei, T., Pavelko, K.D., Lee, J.C., Murray, P.D., and M. Rodriguez (2002) Chemokine expressionin the central nervous system of mice with a viral disease resembling multiple sclerosis: roles of CD4+ and CD8+ Tcells and viral persistence. J. Virol. 76:2217-2224.Rani, M.R., Hibbert, L., Sizemore, N., Stark, G.R., and R.M. Ransohoff (2002) Requirement of phosphoinositide 3-kinase and Akt for interferon-beta -mediated induction of beta -R1 (SCYB11) gene. J. Biol. Chem. 277:38456-38461.Trebst, C., Staugaitis, S.M., Kivisakk, P., Mahad, D., Cathcart, M.K., Tucky, B., Wei, T., Rani, M.R., Horuk, R., Aldape,K.D., Pardo, C.A., Lucchinetti, C.F., Lassmann, H., and R.M. Ransohoff (2003) CC chemokine receptor 8 inthe central nervous system is associated with phagocytic macrophages. Am. J. Pathol. 162:427-438.Huang, D., Tani, M., Wang, J., Han, Y., He, T.T., Weaver, J., Charo, I.F., Tuohy, V.K., Rollins, B.J., and R.M. Ransohoff(2002) Pertussis toxin induced reversible encephalopathy dependent on monocyte chemoattractant protein-1over-expression in mice. J. Neurosci. 22:10633-10642.Kivisäkk, P., Mahad, D.J., Callahan, M.K., Trebst, C., Tucky, B., Wei, T., Wu, L., Baekkevold, E.S., Lassmann, H.,Staugaitis, S.M., Campbell, J.J., and R.M. Ransohoff (2003) Human cerebrospinal fluid central memory CD4+ T-cells:Evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl. Acad. Sci. USA. 2003 June26 [Epub ahead of print].Ransohoff RM, Kivisäkk P, and G. Kidd (2003) Three (or more) ways for leukocytes into the CNS. Nat. Rev. Immunol.3:569-581.146