The primary goal of continuing research on this project is to build upon the current understanding of the structural, molecular and functional properties of retinal interphotoreceptor matrix (IPM) constituents and their interactions with cone photoreceptor cells in healthy and diseased primate retinas. Studies conducted during the current funding period have provided compelling evidence that IPM proteoglycans participate in mediating retinal adhesion and maintaining photoreceptor cell viability in normal retinas. Other studies demonstrated that IPM glycoconjugates are present in vitreous aspirates collected from patients with rhematogenous retinal detachments. Furthermore, distinct compositional changes in IPM glycoconjugates have been identified in human eyes containing macular drusen, extracellular deposits in Bruch's membrane that are a known risk factor for the development of age-related macular degeneration. The emphasis of this proposal is placed on elucidating the molecular composition, structural organization, and functional properties of two unique IPM proteoglycans, designated IPM 150 and IPM 200, in normal, immature, aged and diseased primate retinas. Particular attention will be focused on characterizing fovea-associated IPM proteoglycans. Enriched preparations of insoluble IPM will be utilized to further characterize IPM 150, IPM 200, and other recently identified insoluble IPM glycoconjugates. The complete amino acid and nucleotide sequences of IPM 150 and IPM 200 will be determined and the composition, linkages and sequences of their associated oligosaccharides characterized. The precise substructural distribution of IPM 150 and IPM 200 within the IPM, especially as related to """"""""cone matrix sheaths"""""""", will be assessed immunohistochemically. Definitive information pertaining to the cellular site(s) of synthesis of IPM 150 and IPM 200 and their corresponding mRNAs will be assessed in normal and diseased human retinas, in extraocular tissues and in other species, using in situ hybridization, Northern blot analysis, and immunohistochemistry. Analyses of IPM from human donors with macular drusen will characterize the molecular manifestations of disease-related alterations in these eyes. The molecular bases for retinal adhesion will be pursued both in vitro and in vivo, in an attempt to identify IPM ligands that bind the vitronectin receptor and/or CD44, recently identified adhesion receptors associated with cells that line the interphotoreceptor space. The studies described herein are directed towards providing rigorous analyses of IPM 150 and IPM 200 structure and function. It is anticipated that successful completion of the studies outlined herein will add significantly to the overall understanding of the primate IPM and provide further insight into its involvement in retinal homeostasis, as well as in the etiology of retinal aging and diseases such as age- related macular degeneration.
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