# Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina

> **NIH AG R01** · UNIVERSITY OF VIRGINIA · 2026 · $631,751

## Abstract

PROJECT SUMMARY
The retinal pigmented epithelium (RPE) is an amitotic, long-lived cell type that supports healthy visual function
for numerous decades. The aging retina displays pathologic features that are exaggerated in a complex disease
called age-related macular degeneration (AMD). Progressive degeneration of the aging RPE is a hallmark of
geographic atrophy, a late-stage of AMD that causes vision loss. We recently discovered an excess abundance
of cytosolic complementary DNA derived from the SINE retrotransposon element (RTE) Alu family in the RPE of
human eyes with geographic atrophy and that cytosolic Alu cDNAs are highly cytotoxic to the RPE in animal and
human cell-based studies. These Alu cDNAs are produced via reverse transcription of Alu RNAs by the long-
interspersed nuclear element-1 (L1). We also found that Alu cDNAs trigger the cytosolic escape of mitochondrial
DNA (mtDNA), and together these two cytosolic DNAs collaborate, in mechanistically unclear ways, to activate
a multifaceted innate immune response that results in cell death. To gain a better understanding of the
combinatory impact of Alu cDNAs and mtDNA and their causal contribution to aging in the retina, we will (1)
create temporal, spatial, and sequence topographic maps of Alu cDNA subfamilies and mtDNA in young, healthy
aged, and AMD-affected human eyes; (2) probe the stimuli for and mechanisms of Alu cDNA generation in aging
by investigating whether L1 regulators influence Alu cDNA production and retinal toxicity; and (3) elucidate the
pathway of mitochondrial dysfunction triggered by Alu cDNA and the noncanonical inflammatory pathways
triggered by Alu cDNA and mtDNA joint activity that are responsible for retinal cell death. This proposal is
responsive to RFA-AG-23-015 as it will provide mechanistic insights into how cytosolic Alu cDNAs and mtDNA
mediate interactions of aging hallmarks and modulate healthspan by mapping their sequence and expression
during aging, determining the regulat

## Key facts

- **NIH application ID:** 11307592
- **Project number:** 5R01AG082748-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jayakrishna  Ambati; Bradley David Gelfand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $631,751
- **Award type:** 5
- **Project period:** 2023-08-15T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11307592

## Citation

> US National Institutes of Health, RePORTER application 11307592, Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina (5R01AG082748-04). Retrieved via AI Analytics 2026-05-19 from https://api.ai-analytics.org/grant/nih/11307592. Licensed CC0.

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