# Leber Congenital Amaurosis 8 models and pathogenic mechanisms

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $1,888

## Abstract

Project Summary
Leber congenital amaurosis 8 (LCA8) is the most severe, non-treatable, early-onset (usually at birth) blinding
disease that is caused by recessive mutations in Crumbs homolog 1 (Crb1) gene. About 20% of children
attending schools for the blind around world are affected by LCA. Development of effective, mechanism-based
therapies require models that replicate human LCA8 pathology. Current mouse models have limitations in
reproducing human phenotypes partly due to partial gene ablation in ocular tissues, thus pathogenic
mechanism studies at the cellular and molecular levels are inadequate. The newly-generated, improved mouse
model using conditional ablation of Crb1 and its paralog, Crb2, exhibits main features of LCA8 including thick
retina, indistinct retinal lamination, defects in the retinal pigment epithelium, and most importantly, the early-
onset visual loss at the eye opening stage. Intriguingly, our data also indicate that retinal pathology starts in the
retinal progenitor cells (RPCs), unlike most other types of LCA. Mutant RPCs undergo defective interkinetic
nuclear migration that may alter cellular processes involved in cell proliferation, growth, apico-basal polarity,
and actomyosin cytoskeleton regulation. Additionally, we found that several signaling cascades were severely
altered; decreased Yap signaling essential for the proliferation of the RPCs and cell survival; increased mTOR
pathway implicated in cell growth and proliferation; over-activated RhoA-ROCK signaling regulating
cytoskeleton dynamics by controlling actomyosin assembly. Therefore, we hypothesize that perturbed
Crb1/Crb2 downstream signaling activities play crucial roles in the initial pathogenesis of LCA8 in the RPCs.
To test this, we will first fully assess the development of LCA8 pathology using histological,
immunofluorescence assays along with a non-invasive, longitudinal imaging for quantifying retinal lesions.
Second, we will delineate RPC-specific, cellular and molecular mechanisms underlying LCA8 pathogenesis.
Third, we will define signaling pathway-dependent contributions to LCA8 pathology by genetic and
pharmacological approaches.

## Key facts

- **NIH application ID:** 9876940
- **Project number:** 5R01EY020578-07
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Seo-Hee Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,888
- **Award type:** 5
- **Project period:** 2010-06-01 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876940

## Citation

> US National Institutes of Health, RePORTER application 9876940, Leber Congenital Amaurosis 8 models and pathogenic mechanisms (5R01EY020578-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9876940. Licensed CC0.

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