# Optimizing Models of Non-Coding Genetic Risk in Age-Related Macular Degeneration

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $492,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Genome-wide association studies (GWAS) and other genetic analyses consistently implicate non-coding cis-
regulatory elements (CREs) in age-related macular degeneration (AMD). However, the contribution of CREs to
the risk of developing AMD remains poorly understood because the function these elements has not yet been
directly tested. The barrier for testing AMD-associated CREs is in part due to the challenge of developing
experimentally validated model systems. CREs can be cell-type-specific and are not necessarily conserved
between humans and model organisms. It therefore remains unclear which CREs may be studied in vivo in
transgenic mice versus which require an in vitro human cell system. This gap in knowledge is a significant
obstacle toward understanding the genetic regulation of normal human vision and to understanding the
contribution of specific CREs to AMD. The long-term goal for our research is to understand how genetic variation
within CREs shapes the structure and function of the retina and contributes to the risk of developing AMD and
other disorders of vision. The focused objective of this proposal is to optimize and validate model systems for
studying the function of AMD-associated CREs. The central hypothesis driving this work is that some AMD-
associated CREs will be conserved between humans and mice due to their functional importance in vision. Other
CREs may be human-specific due to their essential roles in the macula, a part of the retina that is not present in
mice. In each of these cases, one or more optimal systems will be required to understand the function of each
AMD-associated CRE. To test this hypothesis, we are pursuing the following specific aims: 1) Determine the
functional conservation of AMD-associated CREs between humans and mice. 2) Test the function of a specific
CRE that is known to be conserved between humans and mice from our preliminary studies in a newly developed
mouse knockout model. 3) Test the requirement of human-specific CREs that are among the leading contributors
to AMD risk, in induced human retinal tissue cultures. Together these experiments will enable discovery of
genetic contributions to human vision and inherited visual diseases that have thus far been inaccessible using
current methods.

## Key facts

- **NIH application ID:** 10343475
- **Project number:** 1R01EY033364-01
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** TIMOTHY JOEL CHERRY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,250
- **Award type:** 1
- **Project period:** 2022-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343475

## Citation

> US National Institutes of Health, RePORTER application 10343475, Optimizing Models of Non-Coding Genetic Risk in Age-Related Macular Degeneration (1R01EY033364-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10343475. Licensed CC0.

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