# Deciphering the mechanisms associated with high-risk AMD genotypes for ARMS2/HTRA1 andComplement Factor H

> **NIH NIH U01** · DOHENY EYE INSTITUTE · 2023 · $382,058

## Abstract

Project Summary
This U01 grant application is submitted in response to RFA EY-21-002 “Age-related Macular Degeneration
(AMD) Integrative Biology Initiative”, with the goal of determining if patient-derived induced pluripotent stem cell
(iPSC)-retinal pigment epithelium (RPE) can be used to discover the underlying pathophysiology of AMD.
Studies from our laboratory as well as those of others strongly support the use of iPSC-RPE to understand how
specific single-nucleotide polymorphisms (SNP) associated with high risk for advanced AMD influences multiple
biological processes in the RPE. Our studies will focus on two SNPs with the highest odds ratio for developing
advanced AMD- Age-Related Maculopathy Susceptibility 2/High Temperature Requirement A1 (ARMS2/HTRA1)
and Complement Factor H (CFH). We will use the iPSC developed by the NEI and the New York Stem Cell
Foundation (NYSCF) and differentiate the parent cells and their reciprocal isogenic lines into RPE using the
protocol established in the Bharti laboratory. The parent/isogenic lines provide an excellent model system for
deciphering the molecular factors that determine how the presence of SNPs in one or both genes affect the
response to stress. We will test the hypothesis that the presence of homozygous risk alleles for either
ARMS2/HTRA1 or CFH, independent and in combination, have a negative impact on the RPE stress response.
Furthermore, each genetic risk profile will have a unique stress response. Our proposed studies will integrate
classical reductionist investigations, coupled with discovery-driven analyses, to test specific hypotheses. Aim 1
will focus on differentiating and characterizing iPSC-RPE cell lines from 10 AMD patients and their isogenic lines.
Aim 2 will test the hypothesis that the presence of AMD high-risk SNPs alter the cellular response to stress by
performing large-scale quantification of proteins and metabolites, coupled with mt functional assays. Parent cells
and their isogenic lines will be compared to determine the impact on metabolism and the stress response in
iPSC-RPE (i) with the CFH high-risk SNP and (ii) for high risk ARMS2/HTRA1, alone or in combination with high
risk CFH. These studies will address how the presence of specific risk variants affect RPE exposed to a
physiologically relevant stress, an important gap in knowledge of AMD pathogenesis. Knowledge about the
molecular details has the potential to lead to development of therapies targeting the primary defect in a
genetically defined population of AMD patients, which in turn, could lead to a “personalized medicine” approach
for treatment of AMD.

## Key facts

- **NIH application ID:** 10707245
- **Project number:** 5U01EY034669-02
- **Recipient organization:** DOHENY EYE INSTITUTE
- **Principal Investigator:** Deborah Ann Ferrington
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $382,058
- **Award type:** 5
- **Project period:** 2022-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707245

## Citation

> US National Institutes of Health, RePORTER application 10707245, Deciphering the mechanisms associated with high-risk AMD genotypes for ARMS2/HTRA1 andComplement Factor H (5U01EY034669-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10707245. Licensed CC0.

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