# Neuroprotection Mechanism for Photoreceptors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $78,953

## Abstract

PROJECT SUMMARY
Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in a variety of retinal degeneration
animal models. In recent years, CNTF secreted from an encapsulated cell device has been evaluated in
several clinical trials, and the FDA has granted this CNTF therapy an Orphan Drug Status for the treatment
of retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD). Yet despite the potential of
CNTF as a broad-spectrum therapeutic agent for different blinding diseases, its mechanisms of action in the
retina remain poorly understood.
We have shown previously that constitutive, high-level expression of CNTF prevents photoreceptor death
but alters retinal gene expression and suppresses visual function. Recently, we have explored the
mechanism of CNTF action using genetic perturbations in an RP mouse model treated with the same
human CNTF used in clinical trials. By performing retinal cell type specific gene deletions, we have shown
that the initial targets of CNTF are Müller glial cells, and without a functional cytokine receptor in Müller glia,
downstream signaling events and CNTF-induced photoreceptor survival are abolished. Although the rod
photoreceptors do not directly respond to exogenous CNTF, they also require a functional cytokine receptor
for survival. Furthermore, we have provided evidence that exogenous CNTF stimulates and amplifies a
signaling loop between Müller glia and photoreceptors to promote neuronal viability. However, despite a
significant improvement in photoreceptor morphology and viability, low levels of exogenous CNTF only
stabilize but do not further enhance retinal function.
The proposed research will combine advanced molecular genetic and system biology approaches to
investigate the mechanisms underlying CNTF-induced neuroprotection in the retina. We will determine the
functions of specific signaling modalities activated by CNTF in rod photoreceptors and Müller glia by using
genetically modified mice. We will analyze CNTF-induced changes at the epigenome and transcriptome
levels in rod cells by comparing wild type and mutant retinas to decipher critical cellular processes affecting
cell survival and function. We will also evaluate the effect of CNTF treatment on cellular metabolism in
diseased retinas and define the signaling effector mediating the effect. The proposed research will advance
our understanding of neuroprotection mechanisms, provide insight into the effects of CNTF in human
retinas, and facilitate the development of more efficacious treatments for retinal degeneration.

## Key facts

- **NIH application ID:** 10462427
- **Project number:** 3R01EY026319-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Xian-Jie Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $78,953
- **Award type:** 3
- **Project period:** 2016-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462427

## Citation

> US National Institutes of Health, RePORTER application 10462427, Neuroprotection Mechanism for Photoreceptors (3R01EY026319-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10462427. Licensed CC0.

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