CADHERIN REGULATION OF AQUEOUS HUMOR OUTFLOW

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Glaucoma, the second leading cause of irreversible blindness in the United States, is a group of disorders characterized by progressive loss of retinal ganglion cells with associated loss of vision that is in most cases coincident with elevated intraocular pressure (IOP)1-3. Today and in the foreseeable future, those with glaucoma are managed clinically with pharmaceutical agents that control IP. Elevated IOP in those with glaucoma appears to be a function of defective regulatory processes mean to maintain normal IOP that result in increased resistance to outflow/4-7. A current area of focus for glaucoma research is to understand the molecular and cellular mechanisms that underlie the regulation of aqueous outflow resistance. In the present proposal, we examine the regulation of aqueous humor in the outflow pathway in a novel manner. We will study a family of transmembrane cell-cell adhesion molecules, the cadherins, in the cells of the human outflow pathway. Cadherins form adheren function complex that in the outflow pathway have only been described at the morphological level. Since homophilic protein:protein interactions of the extracellular domains of cadherins on adjacent outflow cells are critical in the integrity of intercellular junctional complexes (including adherens, occludens and gap), we hypothesize that cadherens contribute significantly to the generation of outflow resistance Our study will examine these proteins at the molecular level and a) identify the subtypes present in both TM and SC cells (normal and glaucomatous), b) analyze effects of pressure/flow on relative expression levels, subcellular distribution and turnover and c) monitor signaling molecules that regulate the formation and remodeling of proteins in the adheren complex. If successful, results obtained from these investigations will provide a basic understanding of the role of cadherin subtypes in aqueous outflow resistance, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations.