# Regulation of Cyclic GMP Synthesis in Photoreceptors

> **NIH NIH R01** · SALUS UNIVERSITY · 2021 · $384,340

## Abstract

PROJECT SUMMARY
Various congenital retinal disorders are “phototransduction diseases”, caused by abnormalities in
photoreceptor signaling mechanisms mediated by cyclic cGMP (cGMP). One of the fundamentals in
photoreceptor signaling and physiology is cGMP synthesis catalyzed by retinal guanylyl (guanylate) cyclase
(RetGC), controlled by calcium, guanylyl cyclase activating proteins (GCAPs), and retinal degeneration 3
(RD3) protein. Defects in RetGC activity and/or regulation cause severe forms of congenital blindness – Leber
congenital amaurosis 1 (LCA1) and dominant cone-rod dystrophy 6 (CORD6). The high importance and the
basic principles of the RetGC regulation in photoreceptor signaling and survival have been established, yet
some key mechanistic aspects remain insufficiently understood. That includes those protein interactions of
RetGC that define its biological function and, when affected, trigger retinal diseases. This proposal, conforming
to the NEI mission to support research with respect to blinding eye diseases, visual disorders and mechanisms
of visual function, is build on recent new advancements in studying RetGC regulation in photoreceptor
physiology and disease: 1) identification of protein determinants critical for RetGC interactions with GCAPs
and RD3; 2) location of RetGC binding domain on RD3; 3) development of a first mouse genetic model for
studying CORD6 degeneration caused by mutation in RetGC1; 4) advancements in RetGC1 gene delivery
mediated by adeno-associated viral (AAV) vectors; and 5) delineating multiple physiological consequences of
mutations in different structural domains of RetGC1 causing LCA1 and CORD6. We here propose a broad
study to evaluate new hypotheses and provide in-depth mechanistic understanding of regulatory processes in
cGMP synthesis, by integrating protein biochemistry, molecular biology, molecular genetics and gene delivery.
Aim 1 will address the molecular mechanisms underlying RetGC regulation by GCAPs and RD3. Aim 2 will
determine how a RetGC1 mutation linked to CORD6 triggers photoreceptor death using a newly developed
transgenic mouse model of CORD6 degeneration. Aim 3 will seek better understanding of molecular and
cellular mechanisms controlled by RD3 in regulation of the RetGC activity. By completing these specific aims,
we expect to reach a deeper and more reliable understanding of how RetGC function and regulation define its
role in normal photoreceptor physiology and in congenital diseases of the retina.

## Key facts

- **NIH application ID:** 10192520
- **Project number:** 5R01EY011522-26
- **Recipient organization:** SALUS UNIVERSITY
- **Principal Investigator:** ALEXANDER M DIZHOOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,340
- **Award type:** 5
- **Project period:** 1996-08-01 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192520

## Citation

> US National Institutes of Health, RePORTER application 10192520, Regulation of Cyclic GMP Synthesis in Photoreceptors (5R01EY011522-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10192520. Licensed CC0.

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