# Use of systems pharmacology to prevent rod and cone photoreceptor degeneration

> **NIH NIH R24** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $1,405,643

## Abstract

ABSTRACT
 An interdisciplinary consortium of investigators from the Departments of Pharmacology and Ophthalmology
at Case Western Reserve University, the Cleveland Louis Stokes VA Medical Center, the Cole Eye Institute at
Cleveland Clinic Foundation, Washington University, Michigan State University, Johns Hopkins University and
ingenious Targeting Laboratory, Inc., proposes "to increase the pace at which basic science discoveries of
disease mechanisms can be translated into therapies for complex visual system disorders and disease", a goal
of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific
partnership will employ its diverse expertise to evaluate potential therapies for retinal diseases in animal models
by using a cutting-edge systems pharmacology paradigm. By screening a combination of G protein-coupled
receptor (GPCR) agonist/antagonist drugs (modulators) for their ability to prevent retinal pathology in animal
models of various rod and cone photoreceptor cell retinopathies, we will identify suitable candidates for future
testing in humans. High resolution imaging methods and transcriptional analysis among other approaches will
be used to monitor the efficacy and safety of these combination therapies. The goals of this project are: Aim 1.
Test in mice the efficacy of a combination of GPCR agonists/antagonists in protecting against light-induced
retinal damage and with either spontaneous rapid or slowly-progressing cone degeneration. Aim 2.
Pharmacologically and genetically validate the involvement and specificity of identified GPCRs and their precise
subcellular localization using knockin mice with T4 lysosome (T4L) fused into their signaling domains and an
antibody we developed against T4L. We also will use the FAST system that allows various genetic outcomes
(from inactivation to overexpression) to be engineered in a single mouse model. Aim 3. Assess the effectiveness
of GPCR therapy in a canine rod-cone retinopathy model. Aim 4. Expand the range of receptor modulators to
include therapeutic antibodies. Fulfilling these interrelated aims will direct our development of more successful
therapies for people with incurable blinding diseases.

## Key facts

- **NIH application ID:** 10145693
- **Project number:** 5R24EY027283-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Krzysztof Palczewski
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,405,643
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145693

## Citation

> US National Institutes of Health, RePORTER application 10145693, Use of systems pharmacology to prevent rod and cone photoreceptor degeneration (5R24EY027283-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145693. Licensed CC0.

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