Recent advances, including work by us and our collaborators, are leading to an increasingly comprehensive and defining concept of the mechanism of aqueous humor secretion by the ciliary epithelial bilayer, comprising the nonpigmented (NPE) and pigmented (PE) ciliary epithelial cells. We propose to develop these ideas further through an integrated program addressing: membrane physiology with molecular, electrophysiological and videomicroscopic techniques; tissue physiology with the unique approach of electron-probe X-ray microanalysis; and whole organ physiology with assessments of intraocular pressure in living animals. The program offers an unusual opportunity to expand to strategies for developing novel, highly specific and more effective pharmacologic interventions to lower aqueous humor secretion and reduce IOP in glaucomatous patients.
Specific aims : (1) For the NPE cells at the aqueous surface, establish the central role of the ClC-3 channel and Cl- release in secretion of aqueous humor. (2) For the PE cells at the opposite (stromal) surface of the tissue, establish the central role of paired Na+/H+ and Cl-/HC03 - exchangers in taking up Cl- from the stroma. (3) For the coordinated bilayer as a whole, establish that the transepithelial balance between secretion and reabsorption varies antero-posteriorly along the surface of the ciliary epithelium, and document that certain drugs can act synergistically both to block secretion at the aqueous surface and to stimulate reabsorption at the stromal surface.
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