# RPE Cell Bystander Effects Contribute to AMD Pathology

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic ab-
normalities and environmental insults. AMD is the leading cause of blindness for Americans over age sixty.
Since smoking, a major cause of oxidative stress, significantly increases the risk of AMD and there is a 20%
higher incidence of smoking in veterans than in the general U.S. civilian population, the VA system will have to
provide care for potentially >7 million AMD cases. The current concepts of AMD recognize that chronic oxida-
tive stress and inflammation (including complement activation) can trigger pathological changes in RPE,
Bruch’s membrane (BrM) and choroid. Major efforts to develop new AMD therapeutics have been focused on
complement inhibitors. However, to date, all targets within the complement cascade have failed. We pose
that one complication not yet considered is the potential issue of intracellular complement signaling. The
overarching goal is to determine how damage signals leading to mitochondrial dysfunction are spread
throughout the RPE monolayer, and to elucidate the contribution of intracellular complement signaling. Using
highly differentiated RPE cells we have made significant progress demonstrating that oxidative stress
changes the cargo in exosomes that are released from cells and that those exosomes induce short- and
long-term changes in recipient RPE. Importantly, we found that long-term changes triggered by exosomes
included changes in mitochondrial homeostasis and have identified potential mediators. Likewise, we
showed that oxidative stress triggers mitochondrial membrane potential and calcium changes in an individual
stressed cell that is then propagated through gap junctions to receptive cells. A receptive cell was identified
as a cell with high baseline calcium, less negative membrane potential and low melanin levels. Based on the
new knowledge identified in the previous funding period, we wish to expand on the following hypotheses. 1)
As it is now accepted that an overactive complement system is tied to AMD incidence, we propose to investi-
gate the contribution of intracellular complement signaling in mitochondrial damage and ensuing pathology.
And 2) as mitochondria are the organelles responsible for energy production and making life/death decisions
in a cell, we wish to determine the contribution of exosomes to the transfer of information to recipient cells.
Two aims were designed to answers those questions. Aim 1 tests the prediction that intracellular calcium
and complement signaling contribute to mitochondrial stress in the RPE network; Aim 2 tests the prediction
that exosomal content alters intracellular milieu resulting in changes in mitochondrial homeostasis in the
RPE network. We will test questions in three sets of cells with different features: ARPE-19, which can easily
be manipulated; second, we will use J and H mitochondrial cybrids, in which the J haplotype is associated
with increased r...

## Key facts

- **NIH application ID:** 10293593
- **Project number:** 5I01BX003050-06
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Baerbel Rohrer
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-07-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293593

## Citation

> US National Institutes of Health, RePORTER application 10293593, RPE Cell Bystander Effects Contribute to AMD Pathology (5I01BX003050-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293593. Licensed CC0.

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