# Role of retinoic acid signaling in fovea development

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $395,258

## Abstract

PROJECT SUMMARY:
The fovea is a highly specialized retinal structure located within the macula responsible for high-
acuity vision, which in humans enables critical tasks such as reading and recognizing faces.
Foveal diseases such as macular degeneration are highly debilitating and often lead to blindness.
However, there are no current available treatments or therapies for fovea-specific disorders. A
major reason underlying this limitation is the lack of suitable experimental systems for foveal
studies, as only a small number of species have fovea-like high acuity areas (HAA). Indeed,
among mammals, only a subset of primates has foveated retinas. However, avian species
including the chick, possess fovea-like HAA and can be used as a powerful model system to study
the molecular underpinnings of fovea formation in vivo. Human stem cell-derived retinal organoids
(hRetOrg) have emerged as a promising in vitro system to study human retinal disorders but
current protocols fail to generate foveae. We have recently found that retinoic acid (RA) signaling
is highly patterned during foveogenesis in humans and is required for HAA formation in the chick.
Our hypothesis is that recapitulation of endogenous patterns of RA signaling in hRetOrg is
sufficient to induce fovea formation. To test this hypothesis, we will utilize the chick system to
elucidate the spatiotemporal properties of RA-dependent fovea induction in vivo (Aim 1);
longitudinally characterize the dynamics of RA signaling and expression profile of RA enzymes
during retinogenesis period in hRetOrg (Aim 2); experimentally manipulate RA signaling to
recapitulate the spatiotemporal patterns of RA found in vivo in the in vitro hRetOrg system (Aim
3). To achieve this we have developed an innovative molecular strategy based on transposon-
and doxycycline-inducible systems for precise spatial and temporal regulation of transgenesis
and optimized high-speed high-resolution imaging analysis of whole chick retinas and 3D
hRetOrg. This effort will not only advance our current understanding of the mechanistic role of RA
signaling as a fovea regulator but also generate an innovative and much needed foveated
hRetOrg system with high translational potential for diseases affecting the fovea through disease
modeling, high-throughput drug screening and as a source of clinically-relevant fovea-specific
cells for transplantation.

## Key facts

- **NIH application ID:** 10759387
- **Project number:** 5R01EY033385-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Susana Isabel M M A da Silva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,258
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10759387

## Citation

> US National Institutes of Health, RePORTER application 10759387, Role of retinoic acid signaling in fovea development (5R01EY033385-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10759387. Licensed CC0.

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