# Mechanism of photoreceptor cell degeneration in animal models of retinal diseases

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $539,089

## Abstract

PROJECT SUMMARY
Our aims are focused on advancing current knowledge on the role of peripherin 2 (Prph2), also called retinal
degeneration slow (RDS), in outer segment (OS) rim and disc formation, and in understanding the pathogenic
mechanisms of PRPH2-associated disease. We use state-of-the-art technologies and our novel knockin
mouse models to learn 1) how different mutations in Prph2 lead to different disease phenotypes; 2) what
contributes to variability among patients carrying the same mutation; 3) what role the Prph2 partner, rod outer
segment membrane protein 1 (Rom1), plays in these events; and 4) how we can shift PRPH2-associated
severe phenotypes to milder ones. PRPH2 mutations lead to retinal diseases ranging from retinitis pigmentosa
(RP) to a variety of macular degenerations (MD) including pattern dystrophy (PD), which often associates with
secondary defects in neighboring tissues such as the retinal pigment epithelium and retinal/choroidal
vasculature. In spite of the scientific progress so far, a therapeutic option suitable for clinical testing has not
yet been developed. This disappointing outcome is further complicated by the diverse role of Prph2 in rods
versus cones, poor genotype-phenotype correlations, vast intrafamilial and interfamilial phenotypic variability,
the involvement of multiple tissues in the disease process, and the need for a precise dose of Prph2 to combat
the devastating effect of haploinsufficiency. Thus a thorough understanding of Prph2-associated disease
mechanisms, an absolute prerequisite for the development of effective therapies, requires precise knowledge
of the differential role of Prph2 in rods versus cones and the processes that link photoreceptor defects with
subsequent toxic effects in other tissues. Our findings suggest that rod-targeted disease (e.g. RP) arises due
to haploinsufficiency while cone-dominant diseases exhibit a more complex and variable pathology associated
with gain-of-function or dominant-negative effects. However, little is known about the link between these
primary defects in photoreceptors and the blinding secondary sequellae or about what causes intrafamilial
phenotypic heterogeneity. For the first time we have generated mouse models that will allow us to address
these questions. In addition, we have developed an outstanding team of investigators comprising recognized
field leaders in photoreceptor cell biology, with researchers skilled in understanding and evaluating choroidal
and retinal vasculature. Our preliminary data support the hypothesis that Rom1 is a key modifier in cases
where there is significant within-mutation disease variability. Aim1 will assess the role of Syn3B interactions
with Prph2/Rom1 and in OS trafficking. Aim 2 will evaluate mechanisms of diversity in Prph2-associated
disease phenotype. Aim 3 will address the role of Rom1 in modulating the disease pathology of Prph2
mutations. In summary, results from this application will facilitate our understanding ...

## Key facts

- **NIH application ID:** 9917217
- **Project number:** 2R01EY010609-23
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** MUAYYAD R AL-UBAIDI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,089
- **Award type:** 2
- **Project period:** 1995-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917217

## Citation

> US National Institutes of Health, RePORTER application 9917217, Mechanism of photoreceptor cell degeneration in animal models of retinal diseases (2R01EY010609-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9917217. Licensed CC0.

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