# Intraocular pressure regulation via ATP-sensitive potassium channels

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $509,859

## Abstract

ABSTRACT
Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor in glaucoma. While the
cause of elevated IOP is commonly attributed to increased resistance at the trabecular meshwork/Schlemm's canal
interface, an expanding body of evidence highlights the potential resistance created by distal portions of the
conventional outflow pathway (Schlemm's canal outer wall, collector channels, and associated deep scleral and
intrascleral vasculature). Perturbations within this region have been shown to contribute towards the pathology of
glaucoma. We have identified a subset of KATP channel openers as novel ocular hypotensive agents that lower IOP
in normotensive animal models (mice, rabbits, non-human primates) by directly affecting the distal portion of the
conventional outflow pathway (herein referred to as the distal outflow pathway). This novel mode of action
provides us with a unique opportunity to study the role of this region in glaucoma while characterizing in detail the
mode of action of this drug class. In addition, we have preliminary data suggesting that KATP channel openers
provide neuroprotection to retinal ganglion cells (RGCs). Based on studies completed in our previous funding
period, the development of an aqueous soluble, therapy friendly form of this drug class (cromakalim prodrug 1;
CKLP1), and new preliminary data presented in this proposal, we hypothesize that KATP channel openers lower
IOP by targeting the vasculature in the distal outflow pathway, facilitating fluid flow through an Erk1/2
mediated signaling cascade. Additionally, we hypothesize that KATP channel openers are also neuroprotective
agents and can protect RGCs from various glaucomatous insults. To test these hypotheses, we propose to
characterize the vasoregulatory role of KATP channels within the distal outflow pathway, define the relevant
molecular events pertaining to the Erk1/2 signaling pathway, determine the neuroprotective properties associated
with KATP channel opening in RGCs, and examine the ocular hypotensive activity of KATP channel openers in
models of glaucoma. New findings from the proposed studies would provide major advancements towards the
goal of understanding the pathophysiology of glaucoma, novel mechanisms that enhance RGC survival, and
characterization of the KATP channel opener prodrug CKLP1 as a potential therapeutic agent for the
management of glaucoma.

## Key facts

- **NIH application ID:** 10219256
- **Project number:** 5R01EY021727-09
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** MICHAEL P. FAUTSCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,859
- **Award type:** 5
- **Project period:** 2011-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219256

## Citation

> US National Institutes of Health, RePORTER application 10219256, Intraocular pressure regulation via ATP-sensitive potassium channels (5R01EY021727-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219256. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*