# Exploring Mechanisms in Retinal Development/Homeostasis, Retinal Immune Surveillance and Diabetic Retinopathy Using Forward Genetics

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $451,000

## Abstract

Project Summary
 Defects in the carefully orchestrated processes of retinal development, homeostasis and retinal immune
surveillance lead or contribute to a wide range of diseases. It is now clear that genetics not only play a role in
these processes but may also modulate diabetic retinopathy. Our short-term goal is to identify and characterize
gene/protein defects and molecular pathways that lead to abnormal retinal development/homeostasis, altered
retinal immune surveillance and modulation of diabetic retinopathy. The long-term goal is to leverage our
research discoveries to understand retinal disease processes, and to identify novel therapeutic opportunities.
 We propose that a high-throughput and unbiased strategy provides an ideal approach to discovery of
gene/phenotype associations in this setting. In collaboration with Nobel laureate Bruce Beutler, we will employ
a robust state-of-the-science and unbiased forward genetics approach, in which thousands of new random
mutations are generated and mice demonstrating retinal anomalies are identified by screening using fundus
photographs and OCT.
 Our approach has significant advantages compared to other existing protocols. Most importantly, ours is
the first and only protocol in which all mice have been pre-genotyped at all mutant loci. In addition, the large
scale of our system and the large pedigree size will also add to the discovery power. Together, these advantages
will allow us to identify and pursue novel gene/phenotype associations related to retinal development,
homeostasis and disease. We have identified over 43 gene-phenotype associations after covering just 8% of the
mouse genome. Of these, 12 genes have weak associations to the retina in the literature, and another 20 genes
have not been reported in association to the retina. This is strong evidence that expanding our screening to
include the remaining 92% of the mouse genome will yield many more gene-phenotype associations related to
retina development, homeostasis and immune surveillance. Of note, our proposal starts by selecting a few of
the most promising genes we have already identified for further study. We will harness the power of
CRISPR/Cas9 gene editing, single cell RNA sequencing, co-immunoprecipitation experiments with highly
sensitive mass spectrometry and proteomics analysis, our recently published light injury model and other
techniques to explore the mechanisms of these associations. We will also apply the streptozotocin model of
diabetic retinopathy to our OCT retinal imaging pipeline to identify genes that can modulate early diabetic
retinopathy. This proposed research will advance our knowledge of retinal health and disease, and we anticipate
that it will lead to the identification of new therapeutic avenues.

## Key facts

- **NIH application ID:** 10316653
- **Project number:** 1R01EY033181-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rafael Ufret-Vincenty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,000
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316653

## Citation

> US National Institutes of Health, RePORTER application 10316653, Exploring Mechanisms in Retinal Development/Homeostasis, Retinal Immune Surveillance and Diabetic Retinopathy Using Forward Genetics (1R01EY033181-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10316653. Licensed CC0.

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