This is a new R01 application to study the molecular events involved in intraocular pressure (IOP) regulation through adenosine-triphosphate-sensitive potassium (KATP) channels. Elevated IOP is the only treatable risk-factor for glaucoma. Unfortunately, the key molecules involved in outflow resistance and IOP control are unknown. Lack of this knowledge has limited the development of pharmacologic agents that would target these processes. We recently identified a key cellular effector of IOP that may lead to new pharmacologic treatment for ocular hypertension and glaucoma. We have found that activation of KATP channels by KATP channel openers diazoxide, nicorandil, and P-1075 lower IOP in a human anterior segment perfusion model. This activation of KATP channels by the pharmacologic openers can be blocked by KATP channel closers, glyburide, and tolbutamide. In addition, treatment with the KATP channel opener diazoxide and the prostaglandin analogue latanoprost increases outflow facility greater than either agent does individually, suggesting that these agents use distinct mechanisms to lower IOP. To date, no studies involving KATP channels have been performed in the trabecular outflow pathway. The opening and closing of KATP channels have been shown to alter cellular contractility and permeability, provide metabolic protection against ischemia and hypoxia, and enhance cellular adaptation to stress in non-ocular tissues. All of these cellular events have been directly or indirectly linked to the cause of glaucoma. We believe that in order to develop pharmacologic agents for the treatment of elevated IOP, we must first identify key intrinsic molecules and physiological mechanisms involved in lowering IOP. Our central hypothesis is that cellular events resulting from KATP channel activation leads to IOP reduction. It is our premise that KATP channel activation leads to a relaxation of the trabecular meshwork resulting in increased permeability, improved fluid flow, augmented outflow facility, and a decrease in IOP. We propose to characterize KATP channel subunit structure, identify cellular pathways activated by KATP channel openers, and determine the physiological function that couples KATP channel opening to increased outflow facility and a lowering of IOP through the trabecular outflow pathway. In addition, we will determine the effect of KATP channel openers on IOP in normal and primary open-angle glaucoma (POAG) eyes. In vivo, we will analyze KATP channel openers and its effect on IOP in C57BL/6 wild-type and specific KATP channel subunit knockout mice. The completion of this proposal will provide a complete descriptive and mechanistic understanding of the role KATP channels have in the trabecular outflow pathway, and will help in evaluating the feasibility of using KATP channel openers as a treatment modality for increasing outflow facility in POAG.
The proposed studies on KATP channels will yield novel information regarding the mechanisms used to lower IOP in normal and POAG eyes. Analysis of KATP channel subunit structure and determination of cellular pathways affected by KATP channel openers will identify novel target molecules to which future therapies can be directed. More importantly, the analysis of KATP channel openers may result in a new class of drugs for the treatment of ocular hypertension and glaucoma.
|Brickshawana, Adipong; Hinson, Shannon R; Romero, Michael F et al. (2014) Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol 13:795-806|
|Hann, Cheryl R; Vercnocke, Andrew J; Bentley, Michael D et al. (2014) Anatomic changes in Schlemm's canal and collector channels in normal and primary open-angle glaucoma eyes using low and high perfusion pressures. Invest Ophthalmol Vis Sci 55:5834-41|
|Winkler, Nelson S; Fautsch, Michael P (2014) Effects of prostaglandin analogues on aqueous humor outflow pathways. J Ocul Pharmacol Ther 30:102-9|
|Chowdhury, Uttio Roy; Holman, Bradley H; Fautsch, Michael P (2013) ATP-sensitive potassium (K(ATP)) channel openers diazoxide and nicorandil lower intraocular pressure in vivo. Invest Ophthalmol Vis Sci 54:4892-9|