# Assessment of the Complement Pathway in a RPE/choroid Tissue Chip

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $1,053,441

## Abstract

The initiators and/or drivers of Age-related Macular Degeneration (AMD) remain elusive. Current knowledge
suggests that interventions in late disease stages may not be as effective as earlier in the disease due to a
“domino effect”, wherein there are many inflammatory factors acting later in the disease. We posit that there is
value in doing proof of mechanism studies to identify biological effects at the early stage of disease. The major
genetic risk factors include CFH on chromosome1 and ARMS2/HTRA1 on chromosome 10. Despite genetic
heterogeneity, most subjects with AMD show common early pathology that include drusen formation and
complement activation. Based on these common features, the core structures affected in AMD that require
further investigation are the RPE, Bruch’s membrane (BrM) and the choroid. The recent discovery of induced
pluripotent stem cell (iPSC) tissue models to study disease mechanisms and the ability to assemble 3D tissues
permit the study of cell-cell interactions. We have designed a 3D tissue chip which includes an RPE monolayer
sitting on a choroid containing endothelial cells, fibroblasts and pericytes which eventually form a BrM to
complete the structure. Since the endothelial cells undergo anastomosis the final choroidal vasculature can be
perfused to more closely mimic the in vivo environment. Our current goal is to utilize this model to characterize
the responses of the RPE-choroid to various environmental stressors under the influence of the CFH and
ARMS2/HTRA1 risk genotypes. Please note, not only can we assemble the 3D oBRB from different donors,
but we can subsequently analyze four different parts; the supernatant in the top compartment (i.e., sub-retinal
space), the flowthrough in the bottom compartment (i.,e, blood supply of the choroid), as well as the two tissue
compartments, RPE/BrM and CC. Aim 1 will characterize the perfused 3D RPE/choroid chip and provide
baseline data for our readouts (gene expression patterns based on scRNA-Seq; extracellular and intracellular
complement activation; BrM formation over time; and extracellular vesicle analysis). In Aim 2, we ask how
these parameters are affected genetic risk factors, assembling the RPE/choroid complex from iPSC cells using
a combination of RPE-risk with choroid-non-risk or vice versa. And finally, in Aim 3, we characterize the
response of the perfused 3D RPE/choroid chip to AMD relevant stressors, smoke, fatty acid exposure and
alteration in flow rate. Overall, our data will provide unique knowledge about the influence of genetic variation
on complement secretion, expression and synthesis of intracellular and extracellular complement from pre-
drusen to post-drusen development, and the proposal’s outcomes will fill a critical gap in our understanding of
genetic variants on RPE complement activity and identify new potential therapeutic targets directed at the RPE
in the early stages of AMD.

## Key facts

- **NIH application ID:** 10943949
- **Project number:** 1R01EY036519-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** John Atkinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,053,441
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943949

## Citation

> US National Institutes of Health, RePORTER application 10943949, Assessment of the Complement Pathway in a RPE/choroid Tissue Chip (1R01EY036519-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10943949. Licensed CC0.

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