Ion gradients established by Na, K-ATPase in the nonpigmented ciliary epithelium (NPE) are vital to the secretion of aqueous humor. We seek to understand the mechanisms that control Na,K-ATPase activity. Regulation of Na,K-ATPase activity in the NPE is a point of control for the aqueous secretion mechanism. Our working hypothesis is that Na,K-ATPase activity, and thus AH secretion, is subject to regulation by Src family tyrosine kinases (SFK). NPE cells are rich in Na,K-ATPase as well as NO synthase and nitric oxide (NO) donors slow aqueous humor secretion. Studies this far suggest locally generated NO reduces NPE Na,K-ATPase activity. Pilot studies indicate NO activates one or more SFKs in the NPE.
In AIM 1 we will test the hypothesis that SFK activation is a step in the pathway for NO regulation of Na,K-ATPase activity in the NPE. By regulating Na,K- ATPase activity and thus aqueous secretion, NO may serve an autocrine function. Preliminary studies show elevated IOP triggers NO generation. Carbonic anhydrase inhibitors (CAIs) reduce the rate of aqueous humor secretion. Although CAIs work by limiting the availability of cellular bicarbonate, their mechanism of action on aqueous secretion is obscure because they are just as effective in species that concentrate bicarbonate in the aqueous humor and those that do not. We have data that suggest bicarbonate transport inhibition activates a pathway that leads to SFK activation and inhibition of Na,K-ATPase activity.
In AIM 2 we will test the hypothesis that interference with cellular bicarbonate regulates Na,K-ATPase activity by a SFK-dependent mechanism in the NPE. Drugs that slow aqueous formation are a proven way to lower IOP in individuals that have primary open angle glaucoma. The number of persons with glaucoma is increasing and in the future there will be a growing need for novel, affordable glaucoma drugs. The studies proposed here will improve our understanding of regulatory mechanisms for aqueous humor formation and may identify targets to consider in the search for new drugs to reduce aqueous production.

Public Health Relevance

Ion gradients established by Na, K-ATPase in the nonpigmented ciliary epithelium (NPE) are vital to the secretion of aqueous humor. We seek to understand the mechanisms that control Na,K-ATPase activity because regulation of Na,K-ATPase activity in the NPE is a point of control for the aqueous secretion mechanism. Our working hypothesis is that Na,K-ATPase activity, and thus AH secretion, is subject to regulation by Src family tyrosine kinases (SFK). We will test whether SFK activation is a step in the pathway for nitric oxide regulation of Na,K-ATPase activity in the NPE. We also will test whether interference with cellular bicarbonate regulates Na,K-ATPase activity by a SFK-dependent mechanism in the NPE. Drugs that slow aqueous formation are a proven way to lower IOP in persons with glaucoma. The number of persons with glaucoma is increasing and in the future there will be a growing need for novel, affordable glaucoma drugs. The studies proposed here will improve our understanding of regulatory mechanisms for aqueous humor formation and may identify targets in the search for new drugs to reduce aqueous production.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006915-23
Application #
8265003
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
1986-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
23
Fiscal Year
2012
Total Cost
$327,240
Indirect Cost
$111,240
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Lee, Jonghwa; Shahidullah, Mohammad; Hotchkiss, Adam et al. (2015) A renal-like organic anion transport system in the ciliary epithelium of the bovine and human eye. Mol Pharmacol 87:697-705
Shahidullah, Mohammad; Mandal, Amritlal; Wei, Guojun et al. (2014) Nitric oxide regulation of Na, K-ATPase activity in ocular ciliary epithelium involves Src family kinase. J Cell Physiol 229:343-52
Sanderson, Julie; Dartt, Darlene A; Trinkaus-Randall, Vickery et al. (2014) Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res 127:270-9
Shahidullah, Mohammad; Delamere, Nicholas A (2014) Connexins form functional hemichannels in porcine ciliary epithelium. Exp Eye Res 118:20-9
Salyer, Sarah A; Olberding, Jordan R; Distler, Anthony A et al. (2013) Vacuolar ATPase driven potassium transport in highly metastatic breast cancer cells. Biochim Biophys Acta 1832:1734-43
Goldman, Aaron; Chen, HwuDauRw; Khan, Mohammad R et al. (2011) The Na+/H+ exchanger controls deoxycholic acid-induced apoptosis by a H+-activated, Na+-dependent ionic shift in esophageal cells. PLoS One 6:e23835
Goldman, Aaron; Shahidullah, Mohammad; Goldman, David et al. (2010) A novel mechanism of acid and bile acid-induced DNA damage involving Na+/H+ exchanger: implication for Barrett's oesophagus. Gut 59:1606-16
Pelis, Ryan M; Shahidullah, Mohammad; Ghosh, Sikha et al. (2009) Localization of multidrug resistance-associated protein 2 in the nonpigmented ciliary epithelium of the eye. J Pharmacol Exp Ther 329:479-85
Shahidullah, Mohammad; To, Chi-Ho; Pelis, Ryan M et al. (2009) Studies on bicarbonate transporters and carbonic anhydrase in porcine nonpigmented ciliary epithelium. Invest Ophthalmol Vis Sci 50:1791-800
Shahidullah, Mohammad; Mandal, Amritlal; Delamere, Nicholas A (2009) Responses of sodium-hydrogen exchange to nitric oxide in porcine cultured nonpigmented ciliary epithelium. Invest Ophthalmol Vis Sci 50:5851-8

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