# The Role of RPE-derived Exosomes in Deposit Formation and ECM Modulation

> **NIH NIH R21** · DUKE UNIVERSITY · 2021 · $194,293

## Abstract

Abstract
The retinal pigmented epithelium (RPE) functions to maintain the outer blood-retinal barrier and to support pho-
toreceptor function, including regeneration of visual pigment and turnover of outer segments. Dysfunction of
the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading
cause of vision loss among older Americans. Given that a major function of the RPE is to process photorecep-
tor outer segments, the proper functioning of the RPE endosomal pathway is important for retinal health. Multi-
ple lines of evidence indicate that one of the major culprits observed in RPE dysfunction is dysregulation in the
endosomal pathway. It is thought that in AMD this dysregulation in RPE cells is at least in part responsible for
the formation of drusen (protein- and lipid-rich extracellular deposits) between the basal lamina of the RPE and
the pentalaminar collagen- and elastin-rich Bruch’s membrane (BrM). At present, the exact mechanisms for
drusen formation are unknown. Since RPE-released exosomes and other extracellular vesicles (EVs) are
essential parts of the endosomal pathway, we hypothesize that exosomes released from stressed RPE cells
are distinct from those released from unstressed RPE cells, and that these exosomes are involved in
the pathognomonic deposit formation and ECM changes that underlie the early and late stages of
AMD. Accordingly, approaches to characterize these vesicles and modulate their release have high potential to
give important insight to disease mechanisms and new treatment targets. Significantly, very little is known
about RPE-released exosomes and other EVs. By evaluating two complementary in vitro and ex vivo AMD
models, our overall goal for this project is to determine the role of exosome secretion in sub-RPE deposit for-
mation and in ECM changes under conditions relevant to AMD, and whether pharmacological or gene
therapy/biological therapeutic interventions are possible. In the first aim, we will characterize and quantify the
protein and lipid composition of sub-RPE deposits, ECM and basal-side exosomes in RPE stressed by patho-
physiological conditions implicated in AMD (oxidative stress, complement dysregulation, and age), while
modulating exosome release by both pharmacological and genetic approaches. In the second aim we will
characterize the protein and lipid content in drusen and BrM from human post-mortem eyes from normal aged
and AMD donors, by exhaustive proteomic and lipidomic analyses with cutting-edge instrumentation and
analysis methodologies. This work serves as a preclinical study and proof of principle to probe the potential of
modulating exosome secretion and target exosome composition as a therapeutic approach for treating AMD.

## Key facts

- **NIH application ID:** 10285774
- **Project number:** 1R21EY033057-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Mikael Klingeborn
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $194,293
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285774

## Citation

> US National Institutes of Health, RePORTER application 10285774, The Role of RPE-derived Exosomes in Deposit Formation and ECM Modulation (1R21EY033057-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285774. Licensed CC0.

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