# Using Forward Genetics to Explore the Genetics and Mechanisms of Early Onset Glaucoma

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $246,000

## Abstract

Project Summary
The pathways regulating the development of early-onset glaucoma are not well understood. Despite
evidence suggesting that a large proportion of early-onset glaucoma cases may have a genetic basis,
known genes only account for about 20% of cases. In fact, only 12 genes have been described so far,
for primary forms of this disease, compared to hundreds for retinal dystrophies. In this complex biological
system, a Forward Genetics approach is an ideal strategy to ask, without preconceptions, which
genes/molecules are important in regulating early-onset glaucoma. Our short-term goal is to identify
and characterize gene/protein defects and molecular pathways that lead to early-onset glaucoma. The
long-term goal is to leverage our research discoveries to understand this blinding disease, improve
screening strategies, and identify novel therapeutic opportunities.
 We propose that a high-throughput and unbiased strategy provides an ideal approach to discovery
of gene/phenotype associations for early-onset glaucoma. In collaboration with Nobel laureate Bruce
Beutler, we have been employing a robust state-of-the-science and unbiased Forward Genetics pipeline
in which random mutations are generated and mice can be screened for signs of glaucoma. We have
already collected retinal images from 6000 mutagenized mice and proposing to use this extensive
database to screen for genes that lead to inner retinal thinning.
 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
glaucoma. In our retinal studies we have identified over 45 gene-phenotype associations after covering
just 5%-8% of the mouse genome. Of these, 20 genes have not been reported to be associated with the
retina. These results attest to the strength of our pipeline. Having an excellent continuous variable
parameter to monitor for early-onset glaucoma (ganglion cell complex OCT measurements) also supports
the feasibility of our proposal.
 We will harness the power of CRISPR/Cas9 gene editing, single cell RNA sequencing, and co-
immunoprecipitation experiments with highly sensitive mass spectrometry and proteomics analysis, and
other techniques to explore the mechanisms of these associations. This proposed research will advance
our knowledge of the genetic basis in early-onset glaucoma. We also anticipate that our results will lead
to the identification of novel diagnostic and therapeutic avenues.

## Key facts

- **NIH application ID:** 10889754
- **Project number:** 1R21EY036238-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rafael Ufret-Vincenty
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $246,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889754

## Citation

> US National Institutes of Health, RePORTER application 10889754, Using Forward Genetics to Explore the Genetics and Mechanisms of Early Onset Glaucoma (1R21EY036238-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889754. Licensed CC0.

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