Pannexin regulation of aqueous humor inflow and outflow

Project Summary

The only approach proven to delay the onset and slow the progression of glaucomatous blindness is to lower the pressure built up within the eye [the intraocular pressure (IOP)] by the formation of the aqueous humor by the ciliary epithelium. Two substances adenosine triphosphate (ATP) and adenosine (formed from ATP) are normally produced by cells in the eye, and participate in the regulation of IOP. Adenosine acts on one surface (the aqueous humor side) of the ciliary epithelium to increase the rate of formation of fluid and increase IOP, while ATP acts on the body side of the ciliary epithelium to reduce the rate of formation of aqueous humor. The delivery of adenosine and ATP to these surfaces ultimately depends on the release of ATP. The aim of this research is to identify how ATP is released at the two surfaces of the ciliary epithelium and also by cells of the aqueous humor outflow pathway, and to use this information to develop a new strategy for lowering IOP. Despite the likely importance of ATP and adenosine in regulating IOP, the mechanisms of cellular ATP release triggering this regulation have been unclear. Our preliminary results are consistent with a role for a newly discovered family of channels in releasing ATP into the aqueous humor, in addition to two other possible channels previously considered. We plan to determine whether ATP is released by different mechanisms at the aqueous humor surface and body surface of the ciliary epithelium and in cells derived from the outflow pathway of aqueous humor. If ATP is indeed delivered to these sites by different mechanisms, the stage would be set for applying ATP faster at one surface and slower at another. Reducing the rate of ATP release at the aqueous surface of the ciliary epithelium and/or increasing the rate of ATP release at the body surface could provide the rational basis for a future novel method of treating glaucoma.