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.
|McLaughlin, Charles W; Zellhuber-McMillan, Sylvia; Macknight, Anthony D C et al. (2007) Electron microprobe analysis of rabbit ciliary epithelium indicates enhanced secretion posteriorly and enhanced absorption anteriorly. Am J Physiol Cell Physiol 293:C1455-66|
|Do, C W; Civan, M M (2006) Swelling-activated chloride channels in aqueous humour formation: on the one side and the other. Acta Physiol (Oxf) 187:345-52|
|Do, Chi Wai; Peterson-Yantorno, Kim; Civan, Mortimer M (2006) Swelling-activated Cl- channels support Cl- secretion by bovine ciliary epithelium. Invest Ophthalmol Vis Sci 47:2576-82|
|Yang, Hui; Avila, Marcel Y; Peterson-Yantorno, Kim et al. (2005) The cross-species A3 adenosine-receptor antagonist MRS 1292 inhibits adenosine-triggered human nonpigmented ciliary epithelial cell fluid release and reduces mouse intraocular pressure. Curr Eye Res 30:747-54|
|Do, Chi Wai; Lu, Wennan; Mitchell, Claire H et al. (2005) Inhibition of swelling-activated Cl- currents by functional anti-ClC-3 antibody in native bovine non-pigmented ciliary epithelial cells. Invest Ophthalmol Vis Sci 46:948-55|
|Do, Chi-Wai; Peterson-Yantorno, Kim; Mitchell, Claire H et al. (2004) cAMP-activated maxi-Cl(-) channels in native bovine pigmented ciliary epithelial cells. Am J Physiol Cell Physiol 287:C1003-11|
|Civan, Mortimer M; Macknight, Anthony D C (2004) The ins and outs of aqueous humour secretion. Exp Eye Res 78:625-31|
|Do, C W; Civan, M M (2004) Basis of chloride transport in ciliary epithelium. J Membr Biol 200:1-13|
|McLaughlin, Charles W; Zellhuber-McMillan, Sylvia; Macknight, Anthony D C et al. (2004) Electron microprobe analysis of ouabain-exposed ciliary epithelium: PE-NPE cell couplets form the functional units. Am J Physiol Cell Physiol 286:C1376-89|
|Civan, Mortimer M (2003) Foreword to symposium ""forty years of epithelial transport-specificity and commonality"": a tribute to Professor Jose A Zadunaisky. J Exp Zool A Comp Exp Biol 300:3-4|
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