The proposed research integrates membrane transport physiology on a cellular level with electron microprobe analyses of cells in intact tissue and novel methods of measuring intraocular pressure (lOP) and aqueous humor flow in the mouse to address the mechanisms of aqueous humor outflow and intraocular pressure. Cell swelling within the trabecular meshwork (TM) and Schlemm's canal (SC) decreases the aqueous humor outflow facility, and cell shrinkage within this small region increases outflow facility. Subtype-specific adenosine receptor agonists also alter outflow and lOP. On the basis of published evidence and our own data, we propose that: (1) The mechanisms and regulatory signaling cascades underlying responses to purinergic drugs and to volume changes are different in SC, juxtacanalicular and TM cells; (2) Probing the responses to purines and to volume changes at cellular, tissue, organ and whole-animal levels, in part with new technology, will provide new understanding of the dynamic control of aqueous humor outflow; (3) An unifying hypothesis, which we shall test, is that the tight junctions between inner-wall Schlemm's canal cells are the rate-limiting barrier to aqueous humor outflow; and (4) Direct study of the cellular dynamics of outflow regulation can generate new approaches for lowering lOP. The major specific aims are to: (1) Develop pharmacologic strategies for differentially swelling/shrinking inner-wall SC and TM cells and to differentiate responses of these cells to subtype-specific adenosine-receptor agonists and antagonists; (2) Identify responses of inner-wall SC, juxtacanalicular and TM cells to volume changes and to adenosine receptor agonists and antagonists in intact tissue; and (3) Test predictions from cellular and tissue studies by analysis of aqueous humor dynamics by measuring lOP and aqueous humor turnover in the mouse.
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