The goal of this project is to develop a molecular understanding of the regulation of aqueous humor outflow facility through the trabecular meshwork. Elevated intraocular pressure, due to reduced trabecular outflow facility, is a major risk factor for the optic neuropathy that produces vision loss in primary open-angle glaucoma. The overall working hypothesis is that the trabecular regulation of extracellular matrix turnover, initiated by the matrix metalloproteinase family, is central to maintaining normal outflow facility. Recent studies support this hypothesis. The specific focus of this application is to evaluate two types of regulation, shown to change metalloproteinase expression, which may provide information used by trabecular cells for the control of outflow facility. 1) Several growth factors and cytokines were identified, which are potent modulators of trabecular metalloproteinase expression. 2) Mechanical stretch/strain of trabecular cells, hypothetically working through their extracellular matrix-integrin-cytoskeleton network modulates trabecular metalloproteinase expression. Both of these modulators will be evaluated for their ability to regulate trabecular outflow facility in a perfused human culture model system. The molecular details and points of convergence and divergence of the signal transduction pathways used by these trabecular modulators will be elucidated. The effects of specific synthetic modifiers of these signal transduction pathways on outflow facility will be determined. These studies will further test the overall working hypothesis. They may elucidate the sensing mechanism(s) utilized by trabecular cells in the endogenous regulation of aqueous humor outflow facility. Development of a more complete picture of the regulation of trabecular outflow facility will greatly enhance our understanding of the functional behavior of trabecular cells. This information may suggest therapeutic possibilities that can be used to control intraocular pressure and may provide new insights into the causes of primary open-angle glaucoma.
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