Glaucoma is a family of diseases affecting 2% of Americans over the age of 40 and is characterized by visual field loss and optic nerve degeneration. The long-term goals of this program are to understand the intrinsic mechanisms that regulate intraocular pressure (IOP), and determine if defects in these mechanisms contribute to the chronic elevation in IOP observed in glaucomatous individuals. Adenosine is considered a 'retaliatory metabolite'providing local regulation during periods of stress. In the eye, administration of adenosine can lower IOP. Progress during the past funding period has shown that: aqueous levels of adenosine are positively correlated with IOP;the activation of adenosine A-1 receptors lowers IOP primarily by increasing total outflow facility;the activation of adenosine A-1 receptors increases conventional outflow facility;however, this increase can not account totally for the increase in facility observed in vivo;in the conventional outflow pathway adenosine A-1 receptor increases facility by a MAP kinase dependent secretion of matrix metalloproteinases, and the administration of glucocorticoids disrupts adenosine receptor-mediated increases in MAP kinase activity and outflow facility in the conventional outflow pathway. Based on these results, we hypothesize that adenosine and its receptors form an autoregulatory system in the eye that is essential for maintaining IOP within normal limits, and in individuals with steroid-induced glaucoma or primary open-angle glaucoma, this autoregulatory system is disrupted leading to elevated IOP. To investigate this hypothesis three specific aims are proposed: 1) determine the mechanisms involved in adenosine-mediated increase in conventional outflow;2) elucidate the mechanisms involved in adenosine regulation of uveoscleral outflow;and 3) determine the mechanisms responsible for glucocorticoid-induced disruption of adenosine-mediated increases in outflow facility. We anticipate that the results of this project will improve our understanding of the intrinsic mechanisms that regulate IOP;identify the sites and cellular events that mediate adenosine-induced increases in outflow facility;provide information on how alterations in adenosine signaling contributes to the development of steroid-induced and primary open-angle glaucoma; and develop a rational basis for the use of adenosine agonists and cell signaling modulators for the treatment of primary open-angle glaucoma.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Agarwal, Neeraj
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Medical University of South Carolina
Schools of Medicine
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