# AMD Mitochondria Modulate Expression of microRNA 135b-5p and 148a-3p in RPE Cybrids: Implications for Age-related Macular Degeneration

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $196,250

## Abstract

Project Summary/Abstract
Age-related Macular Degeneration (AMD) represents a major cause of blindness in the developed world, and
significant research has been devoted to exploring the causes and potential treatments. While the mitochondria
have been found to be of critical importance to the development of AMD, less is known about the exact pathways
through which mitochondria influence nuclear gene expression and disease progression. We have developed a
novel transmitochondrial cybrid model that allows us to generate retinal pigment epithelial cell lines with identical
nuclei, but with mitochondria from different AMD and age-matched normal subjects. Using these cybrids, our
laboratory has discovered that introduction of AMD mitochondria causes cellular apoptosis, oxidative stress and
decreased cell viability. Presently, we are exploring how the mitochondria of AMD patients could cause these
dramatic changes in cybrid cell lines, and how this influence could be modulated to improve cellular health. One
of the potential pathways that we have investigated is the regulation of microRNA. Our preliminary cybrid data
show that introduction of AMD mitochondria causes altered expression of seven microRNA with functions
relevant to AMD pathology. Subsequent work has focused on the targeted downregulation of two overexpressed
microRNA present in the AMD cybrids (miRNA 135b-5p and miRNA 148a-3p). Downregulation of miRNA 135b-
5p leads to decreased expression of genes associated with apoptosis and angiogenesis, while downregulation
of miRNA 148a-3p results in increased expression levels of genes associated with mitochondrial biogenesis and
decreased reactive oxygen species production. These findings demonstrate the effectiveness of microRNA
modulation as a method for improvement of cellular health and potential treatment. Building upon these
preliminary data, our central hypotheses for this grant are that cells with AMD mitochondria (a) exhibit altered
microRNA expression and that (b) modulation of these dysregulated microRNA levels through targeted inhibition
or overexpression will influence gene expression, cellular health and in vitro models of angiogenesis. Further
understanding of the role of microRNA in the AMD model has a significant potential impact for a variety of other
diseases with mitochondrial dysfunction, including Alzheimer’s and Parkinson’s diseases.

## Key facts

- **NIH application ID:** 10597239
- **Project number:** 5R21EY033942-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Vladimir Jivkov Kefalov
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $196,250
- **Award type:** 5
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10597239

## Citation

> US National Institutes of Health, RePORTER application 10597239, AMD Mitochondria Modulate Expression of microRNA 135b-5p and 148a-3p in RPE Cybrids: Implications for Age-related Macular Degeneration (5R21EY033942-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10597239. Licensed CC0.

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