Glaucoma is a common blinding disease affecting over 66 million persons worldwide. However, less than 10% of people develop glaucoma. An effective mechanism must exist to maintain intraocular pressure (lOP) homeostasis. The goal of this project is to understand normal aqueous humor outflow regulation. Our working hypothesis is that the trabecular mesh work(TM) maintains IOP homeostasis by adjusting the outflow resistance in response to sustained changes in IOP. TM cells sense IOP changes as mechanical stretching of the juxtacanalicular ECM, which is the primary source of the outflow resistance. TM cells produce matrix metalloproteinases (MMPs), which initiate juxtacanaficular ECM turnover, and replacement ECM, which adjusts the resistance and maintains lOP homeostasis. We have presented supportive evidence for much of this hypothesis. This proposal is focused on understanding additional molecular details of this complex homeostatic process.
The specific aims i nclude: (1) Identifying the ECM macromolecules that are degraded by the MMPs in response to elevated lOP or stretch. A combination of proteomics and traditional protein analysis will be used. (2) Identifying the ECM macromolecules made to replace those turned over in this homeostatic adjustment process. Gone microarrays, quantitative reverse transcription polymerase chain reaction (RT-PCR) and protein analysis will be used. (3) Identify specific TM molecules that contribute directly to the outflow resistance. (4) Identify signal transduction pathways involved in lOP/stretch responses and define lOP/stretch sensing mechanism. Perfused anterior segment organ and stretched TM cell cultures will serve as model systems. A detailed molecular picture of the lOP homeostasis mechanism should provide approaches for developing improved and targeted treatments to ameliorate this common blinding disease.
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