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Neuroprotection Mechanism for Photoreceptors

光感受器的神经保护机制

基本信息

批准号：
9918918
负责人：
Xian-Jie Yang
金额：
$ 56.7万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918918
关键词：
ATAC-seq Ablation Affect Age related macular degeneration Animal Model Biochemical Cell Survival Cell physiology Cells Cellular Morphology Cessation of life Ciliary Neurotrophic Factor Ciliary Neurotrophic Factor Receptor Clinical Trials Complex Cytokine Receptors Data Development Devices Disease Dominant-Negative Mutation Encapsulated Epigenetic Process Equine mule Event Gene Deletion Gene Expression Genes Genetic Glaucoma Goals Grant Growth Factor Human IL6ST gene Investigation Knock-out MAP2K1 gene Mediating Metabolism Mitochondria Modality Modeling Molecular Molecular Genetics Morphology Muller&apos s cell Mus Mutation Neuroglia Neurons Neuroprotective Agents Nonexudative age-related macular degeneration Orphan Drugs Outcome Pathway interactions Perception Photoreceptors Play Research Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rod Role STAT3 gene Signal Transduction Systems Biology Testing Therapeutic Agents Treatment Factor Vertebrate Photoreceptors Vision Visual impairment cell type cytokine cytokine receptor gp130 epigenome genetic approach glial activation improved inhibitor/antagonist insight mouse model mutant neuroprotection novel therapeutics prevent public health relevance receptor retinal neuron retinal rods transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): 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 Müler 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 genetics 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.