# Discovery of Biomarkers for Age-Related Macular Degeneration

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $374,070

## Abstract

Project Summary/Abstract
The complement system is critical for rapid detection and clearance of pathogens and immune complexes.
Distinction between self and nonself is conferred by regulator proteins, which downregulate complement
activation on host cells. Complement dysregulation is involved in several inflammatory conditions, including
age-related macular degeneration (AMD). Deficiencies or mutations in specific complement proteins are linked
to increased risk of developing AMD, and complement-targeted therapeutics have shown promise in treating
AMD. In addition, it is critical to be able to monitor the onset and progression of AMD, as aberrant complement
activation occurs on the retinal pigmented epithelium (RPE) in AMD patients. Complement proteins and
regulators are constituents of drusen, including the terminal product C3d that remains covalently attached on
surfaces on which complement has been activated. Our goal is to develop low-molecular mass chemical
compounds and peptides that have strong binding affinities for C3d and fluorescence properties. These
molecules will have potential as quantifiable biomarkers of complement activation in the eye and as
diagnostics for early stage AMD. Our methods are computational and experimental. We will use
pharmacophore-based virtual high-throughput screening, and protein-ligand docking to discover small
chemical compounds with predicted binding affinities for C3d and intrinsic fluorescence. We will also use
peptide design principles to design peptides with attached clinically-approved fluorophores that have predicted
binding affinities for C3d. Both approaches are based on the interactions of C3d with its receptor, complement
receptor 2 (CR2), and complement regulator Factor H (FH), using crystallographic structures and molecular
dynamics simulations. We will test our computationally predicted C3d ligands, using an in vitro direct binding,
biochemical and functional assays, and we will examine their photophysical properties using fluorescence
spectroscopy. We will then evaluate the efficacies of the C3d ligands with highest potency and optimal
fluorescence properties in human retinal pigmented epithelial cell-based assays. Finally, we will test the most
efficacious ligands in histological sections of drusen-laden retinal tissues from non-human primate models of
AMD, as well as using retinal sections from human AMD eyes. The proposed studies will generate data for a
more focused study to evaluate a lead compound in animal models.
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## Key facts

- **NIH application ID:** 9998996
- **Project number:** 5R01EY027440-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Valentine Vullev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,070
- **Award type:** 5
- **Project period:** 2017-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998996

## Citation

> US National Institutes of Health, RePORTER application 9998996, Discovery of Biomarkers for Age-Related Macular Degeneration (5R01EY027440-04). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/9998996. Licensed CC0.

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