The proposed research involves integrating membrane physiology and a novel method of measuring intraocular pressure 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 (C), and cell shrinkage within this small region increases C. Subtype-specific adenosine agonists have also been reported to alter outflow. On the basis of published evidence and our own data, we propose that: (1) TM-cell swelling directly and indirectly modulates outflow; (2) SC-cell swelling also alters the resistance to flow across the SC inner wall; (3) adenosine and ATP receptors modulate cell volume regulation of TM and SC cells; (4) the mechanisms and/or regulation of cell volume control are different in TM and SC cells; and (5) the novel application of servo-null micropipette technology to measure IOP in the mouse will permit direct extension of the membrane physiology to in vivo physiology. The program provides an unusual opportunity for integrating cellular and whole-animal techniques in developing novel pharmacologic interventions for reducing intraocular pressure (IOP) in treating glaucoma and in studying targeted genetic mouse models of aqueous humor outflow.
The specific aims are to: (1) Identify the mechanisms and regulation of cell volume control of human TM and SC cells and immortalized mouse TM cells; (2) Determine the actions and identity of the purinergic receptors and ectoenzymes responsible for modulating the cell volume mechanisms and regulations in these cells; and (3) Extend the cell studies to analysis of aqueous humor dynamics with the servo-null micropipette system (SNMS) we have developed, which provides the first and only reliable approach for measuring IOP in the mouse.
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