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)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
Dahrouj, Mohammad; Alsarraf, Oday; Liu, Yueying et al. (2013) C-type natriuretic peptide protects the retinal pigment epithelium against advanced glycation end product-induced barrier dysfunction. J Pharmacol Exp Ther 344:96-102
Webb, Jerry G; Yang, Xiaofeng; Crosson, Craig E (2011) Bradykinin activation of extracellular signal-regulated kinases in human trabecular meshwork cells. Exp Eye Res 92:495-501
Ablonczy, Zsolt; Dahrouj, Mohammad; Tang, Peter H et al. (2011) Human retinal pigment epithelium cells as functional models for the RPE in vivo. Invest Ophthalmol Vis Sci 52:8614-20
Crosson, Craig E; Mani, Santhosh K; Husain, Shahid et al. (2010) Inhibition of histone deacetylase protects the retina from ischemic injury. Invest Ophthalmol Vis Sci 51:3639-45
Ablonczy, Zsolt; Prakasam, Annamalai; Fant, James et al. (2009) Pigment epithelium-derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor-R2 signaling through gamma-secretase. J Biol Chem 284:30177-86
Husain, Shahid; Potter, David E; Crosson, Craig E (2009) Opioid receptor-activation: retina protected from ischemic injury. Invest Ophthalmol Vis Sci 50:3853-9
Webb, Jerry G; Yang, Xiaofeng; Crosson, Craig E (2009) Expression of the kallikrein/kinin system in human anterior segment. Exp Eye Res 89:126-32
Husain, Shahid; Crosson, Craig E (2008) Role of PKCepsilon in PGF2alpha-stimulated MMP-2 secretion from human ciliary muscle cells. J Ocul Pharmacol Ther 24:268-77
Husain, Shahid; Yates, Phillip W; Crosson, Craig E (2008) Latanoprost-induced changes in rat intraocular pressure: direct or indirect? J Ocul Pharmacol Ther 24:367-72
Ablonczy, Zsolt; Crosson, Craig E (2007) VEGF modulation of retinal pigment epithelium resistance. Exp Eye Res 85:762-71

Showing the most recent 10 out of 43 publications