Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY/ABSTRACT In primary open angle glaucoma, elevated intraocular pressure (IOP) is associated with abnormally increased resistance to aqueous humor (AH) outflow. Due to the complex pathogenesis of glaucoma, the exact mechanism for increased resistance to AH outflow and changes in vascular function is yet to be fully determined. Evidence of the presence of a functional trans-sulfuration pathway in mammalian tissues has stimulated a surge of interest in the biological significance and role of hydrogen sulfide (H2S) in ocular function and disease. In a previous study we showed evidence that H2S (using H2S-releasing compounds as tools) can lower IOP in normotensive rabbits. Furthermore, we reported that H2S can enhance aqueous humor outflow, an effect that is mediated via the conventional pathway. However, the exact mechanism of action of H2S on elevated IOP and aqueous humor dynamics is unclear. The goal of the present proposal is to understand the role of H2S in the pathway and processes involved in the regulation of IOP in glaucoma. Specifically, we will evaluate the physiological/pharmacological action of H2S (using H2S-releasing compounds) on an experimentally-induced animal model of glaucoma and will also determine the role of the endogenous pathway for the biosynthesis of H2S in the maintenance of IOP in this model. Furthermore, we will investigate the cellular mechanism/s of action of exogenously-administered H2S and endogenously-produced H2S on pathways involved in the outflow of IOP and neurodegenerative changes in glaucoma. In summary, studies designed in the present proposal will address the following questions: i) What is the effect of topically instilled H2S (using H2S-releasing compounds as gas donors) on elevated IOP? (ii) Are biosynthetic enzymes for H2S production (CBS, CSE, 3MST) involved in the release and/or availability of H2S in the ciliary artery, ciliary epithelium, iris, TM and neural retina in control and experimental animals with glaucoma? (iii) Does the concentration of H2S in tissues (ciliary artery, ciliary epithelium, iris, TM and neural retina) correlate with protein/mRNA expression levels of biosynthetic enzymes (CBS, CSE and 3MST) in control and experimental animals with glaucoma? (iv) Does the pathway leading to H2S production altered by elevated pressure in the TM using the human anterior segment organ culture model? (v) Does the IOP-lowering action of H2S (administered as H2S-releasing compounds) involve changes in TM morphology and MMP-initiated ECM turnover? (vi) Does the H2S-mediated changes in IOP mitigate some of the neurodegenerative changes observed in glaucoma? What are the mechanism/s involved? We anticipate that data obtained from the present study may also reveal a novel role for H2S in the pathophysiology and/or pharmacology of the anterior uvea and posterior segment of the eye.
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