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

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THE HOLLYFIELDLABORATORYPROJECT SCIENTISTSVera Bonilha, Ph.D.Quiyun Chen, Ph.D.Mary E. Rayborn, M.S.Preenie Senanayake, Ph.D.OPHTHALMOLOGY FELLOW/RESIDENTKo NakataLEAD RESEARCH TECHNOLOGISTKaren Shadrach, M.S.COLLABORATORSDean Bok, Ph.D. 1Anthony Calabro, Ph.D. 2John W. Crabb, Ph.D. 3Vincent Hascall, Ph.D. 2Motohiro Kamei, M.D. 4Ronald Midura, Ph.D. 2Daniel Organisciak, Ph.D. 5Neal Peachey, Ph.D. 3Elisabeth Rungger, Ph.D. 6Hiro Sakaguchi, M.D. 4Robert G. Salomon, Ph.D. 71Jules Stein Eye Inst., Univ.of California, Los Angeles2Dept of Biomedical Eng.,CCF3Dept of Ophthalmic Res.,Cole EyeInst., CCF4Osaka Univ. Med. Sch.,Osaka, Japan5Dept. of Biochem./Mol. Biol.,WrightState Univ., Dayton, OH6Univ.of Geneva, Dept. ofOphthalmology,Geneva, Switzerland7Dept. of Chemistry, CaseWestern ReserveUniv., Cleveland, OHCenter forOphthalmic ResearchIPM-Specific Glycoprotein andProteoglycan Genes as Candidates forRetinal Disease and Drusen Studies inAge-Related Macular DegenerationThe interphotoreceptor matrix (IPM) is thepart of the eye that ophthalmologists callthe subretinal space, the compartmentlocated between the outer retinal surface and theapical border of the retinal pigment epithelium(RPE). Our laboratory focuseson the IPM and its role inhealth and disease. This highlyspecialized extracellular matrixlinks the retina and the RPE.Structure-function activities,such as transport and communicationbetween these twotissues, photoreceptor protection,retinal attachment, andsynthesis and secretion ofvarious molecules, occur at thisinterface. The molecularinteractions responsible forthese activities are not known,but our laboratory recentlyidentified two unique proteinsin the IPM: SPACR(SialoProtein Associated withCones and Rods) was identifiedin the human and monkey(primates) IPM as a glycoproteinand in nonprimates (bovine, mouse and rat)as a proteoglycan; and a novel protein we namedSPACRCAN was identified as a chondroitinsulfate proteoglycan in both primates andnonprimates. The function of these highlyconserved IPM moleculesremains to be determined.We are defining therole of hyaluronan (HA), aglycosaminoglycan that isproposed as the basicorganizer of the IPM, byestablishing the distributionand regulation of thespecific hyaluronansynthases (HASs) thatcontribute HA to thiscompartment. With thisapproach, we are alsodefining the role of twoplasma membranereceptors for HA presenton cells bordering theIPM: RHAMM, localizedto the RPE’s apicalmembranes; and CD44,localized to theJoe G. Hollyfield, Ph.D.Continued on Page 161Marmorstein, A.D., Marmorstein, L.Y., Rayborn, M., Wang, X., Hollyfield, J.G., and K. Petrukhin (2000)Bestrophin, the product of Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateralmembrane of the retinal pigment epithelium. Proc. Nat. Acad. Sci. USA 97:12758-12763.Sakaguchi, H., Miyagi, M., Shadrach, K.G., Rayborn, M.E., Crabb, J.W., and J.G. Hollyfield (2002)Clusterin is present in drusen in age-related macular degeneration. Exp. Eye Res. 74:547-549.Marmorstein, A.D., Marmorstein, L.Y., Sakaguchi, H., and J.G. Hollyfield (2002) Spectral profiling ofautofluorescence associated with lipofuscin, Bruch’s Membrane, and sub-RPE deposits in normal andAMD eyes. Invest. Ophthalmol. Vis. Sci. 43:2435-2441.Nishiyama, K., Sakaguchi, H., Hu, J.G., Bok, D., and J.G. Hollyfield (2002) Claudin localization in ciliaof the retinal pigment epithelium. Anat. Rec. 267:196-203.Crabb, J.W., Miyagi, M., Gu, X., Shadrach, K., West, K.A., Sakaguchi, H., Kamei, M., Hasan, A., Yan,L., Rayborn, M.E., Salomon, R.G., and J.G. Hollyfield (2002) Drusen proteome analysis: an approach tothe etiology of age-related macular degeneration. Proc. Natl. Acad. Sci. USA 99:14682-14687.Chen, Q., Lee, J.W., Nishiyama, K., Shadrach, K.G., Rayborn, M.E., and J.G. Hollyfield (2003) SPACR-CAN in the interphotoreceptor matrix of the mouse retina: molecular, developmental and promoter analysis.Exp. Eye Res. 76:1-14.160
Continued from Page 160microvillae of retinal Müller cells. We are testingthe hypothesis that HA in the IPM is the productof the combined synthetic activities of HAS-1,-2, and -3. We are also interested in establishingwhether HA recovery from the IPM fordegradation is mediated by CD44 and/orRHAMM; for this, we will analyze HA recoveryin CD44- and RHAMM-knockout mice.An ongoing focus is to define in molecularterms the linkage between the accumulation ofsoft drusen below the RPE in the macula and theincreased risk of developing age-related maculardegeneration (AMD). The presence of softdrusen in the macula is the hallmark risk factorfor developing AMD. Surprisingly little is knownof the origin or composition of drusen. To thisend, a novel method for drusen isolation has beendeveloped that allows the collection of microgramquantities of drusen from donor eye tissue.At the time of isolation, different drusen subtypescan be identified and separated for use in studiesthat will characterize their molecular composition.Because of the relationship of drusen andAMD, understanding the composition of differentdrusen subtypes will provide important informationon possible pathways that are causallyinvolved in drusen development. Novel proteinsor common modifications of proteins present indrusen should provide insight as to potential drugtargets of therapeutic agents to treat AMD.161
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