Neuroprotection Mechanism for Photoreceptors

光感受器的神经保护机制

基本信息

批准号：
9263962
负责人：
Xian-Jie Yang
金额：
$ 38.5万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263962
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 Orphan Drugs Outcome Pathway interactions Perception Photoreceptors Play Research Retina Retinal Retinal Degeneration Retinal Diseases Retinitis Pigmentosa 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.

描述（由申请人提供）：睫状神经营养因子（CNTF）在多种视网膜变性动物模型中充当有效的神经保护剂近年来，从封装细胞装置分泌的CNTF已在多项临床试验中进行了评估，FDA也对其进行了评估。尽管 CNTF 具有治疗色素性视网膜炎 (RP) 和干性年龄相关性黄斑变性 (AMD) 的潜力，但已授予该 CNTF 疗法孤儿药地位。 CNTF 是一种针对不同致盲疾病的广谱治疗剂，但其在视网膜中的作用机制仍知之甚少，我们之前已经表明，CNTF 的组成型高水平表达可以防止光感受器死亡，但会改变视网膜基因表达并抑制视觉功能。我们在用临床试验中使用的相同人类 CNTF 治疗的 RP 小鼠模型中利用遗传扰动探索了 CNTF 的作用机制。 CNTF 的目标是 Müller 胶质细胞，如果 Müller 胶质细胞中没有功能性细胞因子受体，下游信号传导事件和 CNTF 诱导的光感受器存活将被取消，尽管视杆光感受器不直接对外源性 CNTF 做出反应，但它们也需要功能性细胞因子受体。此外，我们提供的证据表明，外源性 CNTF 刺激并放大了穆勒神经胶质细胞和光感受器之间的信号环路，以促进神经元的活力。光感受器形态和活力的改善，低水平的外源性 CNTF 仅稳定但不会进一步增强视网膜功能。我们将确定先进的分子遗传学和系统生物学方法相结合，以研究 CNTF 诱导的视网膜神经保护机制。通过使用转基因小鼠，我们将分析 CNTF 诱导的视杆细胞表观基因组和转录组水平的变化。通过比较野生型和突变型视网膜来破译影响细胞存活和功能的关键细胞过程，我们还将评估 CNTF 治疗对患病视网膜细胞代谢的影响，并确定介导该作用的信号传导效应器。神经保护机制，深入了解 CNTF 对人类视网膜的影响，并促进开发更有效的视网膜变性治疗方法。