Neuroprotection Mechanism for Photoreceptors

光感受器的神经保护机制

• 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
• 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' 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

 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得到评估，FDA已授予这种CNTF疗法孤儿药地位，用于治疗色素性视网膜炎（RP）和干性年龄相关性黄斑变性（AMD）。然而，尽管 CNTF 具有作为不同致盲疾病的广谱治疗剂的潜力，但其在视网膜中的作用机制仍然知之甚少。我们之前已经证明，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。最近，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。通过进行视网膜细胞类型特异性基因删除，我们发现CNTF的最初目标是Müller神经胶质细胞，并且Müller神经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被废除。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才能生存。此外，我们提供的证据表明，外源性 CNTF 刺激并放大穆勒神经胶质细胞和光感受器之间的信号环路，以促进神经元活力。然而，尽管光感受器形态和活力显着改善，低水平的外源性CNTF只能稳定视网膜功能，而不能进一步增强视网膜功能。拟议的研究将结合先进的分子遗传学和系统生物学方法来研究 CNTF 诱导视网膜神经保护的机制。我们将通过使用转基因小鼠来确定 CNTF 在视杆光感受器和米勒神经胶质细胞中激活的特定信号传导模式的功能。我们将通过比较野生型和突变型视网膜来分析 CNTF 诱导的视杆细胞表观基因组和转录组水平的变化，以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，并确定介导该效应的信号传导效应器。拟议的研究将增进我们对神经保护机制的理解，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。