# Modeling CRB1-related retinal disease using 3-D human retinal organoids

> **NIH NIH R21** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $209,740

## Abstract

Recessive mutations in CRB1 cause Leber Congenital Amaurosis 8 (LCA8) and Retinitis
Pigmentosa 12 (RP12). Both diseases are currently untreatable, leading to retinal
blindness at birth (LCA8) or at young adulthood (RP12). CRB1 is a single-spanning
transmembrane protein homologous to Drosophila Crumbs (Crb). Crb family proteins
contain a small intracellular domain and a large extracellular domain, and execute their
functions through protein interactions. Crb proteins interact with PDZ- and FERM-
domain proteins through its intracellular domain, whereas form homodimer through its
extracellular domain. Crb proteins have multiple cellular functions: an apical determinant
essential for apicobasal polarity and cell adhesions, and a regulator of supracellular
actomyosin cable in morphogenesis. Crb proteins are also involved in cell signaling
pathways, including Hippo/YAP/TAZ, Notch1, Wingless (Wnt), and mTOR. None of
these functions have been assessed in CRB1-deficient human retinal cells. In mice,
Crb1 is found in the subapical region of retinal progenitor cells and in the outer limiting
membrane of the adult retina. In contrast to early-onset blinding LCA8, Crb1-knockout
mice only display late-onset mild retinal phenotypes, indicating limitations of mouse
models in studying the mechanisms of CRB1-associated retinal disease. Collectively, it
is still unclear how CRB1 mutations affect human retinal cells.
The goal of this study is to determine molecular functions of CRB1 in pluripotent stem
cell-derived human retinal cells. We hypothesize that CRB1 regulates apicobasal polarity
and cell adhesions in human neuroretinal progenitors; CRB1 mutations affect retinal
epithelial structure leading to differentiation defects and degenerations. We will 1)
elucidate the functions of CRB1 in the regulation of apicobasal polarity, cell adhesions,
and differentiation in human neuroretinal tissue; and 2) determine CRB1 interactome
and trafficking in human retinal cells. Accomplishments of the studies will move a step
closer toward therapeutic development for CRB1-associated retinal disease.

## Key facts

- **NIH application ID:** 9986755
- **Project number:** 5R21EY029806-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** WEI LIU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,740
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986755

## Citation

> US National Institutes of Health, RePORTER application 9986755, Modeling CRB1-related retinal disease using 3-D human retinal organoids (5R21EY029806-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986755. Licensed CC0.

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