Metabolism and neuronal viability of the retina

视网膜的新陈代谢和神经元活力

• 批准号: 10522694
• 负责人: Xian-Jie Yang
• 金额: $ 39万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522694
• 关键词: Ablation; Acute; Age related macular degeneration; Anabolism; Animal Model; Aspartic Acid; Astrocytes; Biochemical; Biological Assay; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cellular Morphology; Chronic; Ciliary Neurotrophic Factor; Clinical Trials; Consumption; Cytokine Signaling; Data; Development; Disease; Dose; Endothelial Cells; Energy Supply; Engineering; Enzymes; Event; Excision; Exposure to; Gene Deletion; Genetic Transcription; Glaucoma; Hour; Human; Image; Investigation; Knowledge; Lactate Dehydrogenase; Maintenance; Mediating; Medicine; Metabolic; Metabolic Pathway; Metabolism; Microglia; Mitochondria; Modeling; Molecular; Molecular Genetics; Morphology; Muller' s cell; Mus; Mutation; Neurons; Neuroprotective Agents; Nuclear; Outcome; Oxidation-Reduction; Perception; Persons; Phosphorylation; Photoreceptors; Play; Production; Proteins; Quality of life; Recombinant adeno-associated virus (rAAV); Recombinants; Research; Resolution; Retina; Retinal Degeneration; Retinal Dystrophy; Retinitis Pigmentosa; Rod; Role; STAT3 gene; Signal Transduction; Stat3 protein; Testing; Tissues; Treatment Factor; Viral; Viral Vector; Vision; Visual impairment; Work; aerobic glycolysis; cell type; chemokine; cytokine; cytokine receptor gp130; density; effective therapy; efficacious treatment; genetic analysis; genetic approach; improved; inhibitor; insight; intravitreal injection; metabolomics; mouse model; mutant; neuron loss; neuronal survival; neuroprotection; novel; novel therapeutic intervention; preservation; prevent; resilience; response; retinal neuron; retinal rods; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Retinal dystrophy-caused vision impairment severely impacts the quality of life for millions of people world- wide. Despite advances in recent decades, current medicine still lacks safe and effective treatments for many blinding diseases. Neuroprotective therapies aimed at delaying neuronal loss and preserving visual function could, therefore, be a useful strategy for treating slow-progressing blinding diseases such as age-related macular degeneration and glaucoma. The cytokine ciliary neurotrophic factor (CNTF) is known to act as a potent neuroprotective agent in a variety of retinal degeneration models. However, chronic exposure to high doses of CNTF results in the suppression of visual function in spite of preventing neuronal death. In order to leverage the beneficial while avoiding the detrimental effects of CNTF, it is critical to understand CNTF signal- induced cellular events in the retina. To provide greater insight into ongoing CNTF clinical trials aimed at treating blinding diseases, we performed molecular genetic analyses in mouse retinal degeneration models infected with a viral vector we engineered to express the same human recombinant CNTF being used in clinical trials. We demonstrated that CNTF initially targets Muller glia, which in turn activate a signaling loop between Muller glia and photoreceptors, leading to photoreceptor survival. We also showed that CNTF signaling rapidly and extensively alters the retinal transcriptome, which may underlie the CNTF-mediated suppression of visual function. In addition, we have demonstrated that removal of a cytokine signaling inhibitor in rod photoreceptors is sufficient to enhance their survival in the absence of exogenous CNTF, indicating that modulation of endogenous cytokine signaling can promote photoreceptor viability. Moreover, our recent study has revealed that CNTF treatment profoundly impacts retinal metabolism, resulting in enhanced aerobic glycolysis and anabolism, elevated energy production, and restored retinal redox status. The proposed research will combine molecular and biochemical approaches to further our understanding on the cellular process elicited by CNTF in the retina. We will examine cell type-specific transcriptomic changes and altered metabolic pathways to fully assess effects of CNTF treatments on various cell types. We will evaluate the role of a key glycolytic enzyme in photoreceptor maintenance and survival. We will also determine the distinct functions of cytokine signaling components involved in the CNTF-induced metabolic changes. Outcomes of the proposed research will advance our knowledge of neuroprotection mechanisms, especially the role of metabolism in sustaining neuronal survival, and thus facilitate the development of more efficacious treatments for retinal degeneration.

项目摘要 视网膜营养不良引起的视力障碍严重影响了数百万人世界的生活质量 - 宽的。尽管最近几十年的进步，目前的医学仍然缺乏许多人的安全有效治疗 盲目的疾病。旨在延迟神经元丧失和保留视觉功能的神经保护疗法 因此，可能是治疗缓慢产生的盲目疾病（例如与年龄有关的）的有用策略 黄斑变性和青光眼。细胞因子睫状神经营养因子（CNTF）被称为 各种视网膜变性模型中有效的神经保护剂。但是，长期接触高 CNTF的剂量尽管可以预防神经元死亡，但仍会抑制视觉功能。为了 在避免CNTF的有害影响的同时利用有益的有益，了解CNTF信号至关重要 诱导视网膜中的细胞事件。 为了对正在进行的CNTF临床试验进行更深入的了解，旨在治疗盲目疾病，我们进行了 用病毒载体感染的小鼠视网膜变性模型中的分子遗传分析我们设计了 表达在临床试验中使用的相同重组CNTF。我们证明了CNTF 最初是针对Muller Glia，该胶质胶质又激活了Muller Glia和感光器之间的信号回路 导致光感受器的存活。我们还表明，CNTF信号迅速和广泛地改变了 视网膜转录组，这可能是CNTF介导的视觉功能抑制的基础。另外，我们 已经证明，去除杆感光器中的细胞因子信号抑制剂足以增强 它们在没有外源CNTF的情况下生存，表明内源性细胞因子信号的调节 可以促进感受器的生存能力。此外，我们最近的研究表明，CNTF治疗深刻 影响视网膜代谢，导致有氧糖酵解和合成代谢增强，能量升高 生产并恢复了视网膜氧化还原状态。 拟议的研究将结合分子和生化方法，以进一步了解我们对 CNTF在视网膜中引起的细胞过程。我们将检查细胞类型特异性的转录组变化 并改变了代谢途径，以完全评估CNTF处理对各种细胞类型的影响。我们将 评估关键糖酵解酶在光感受器维持和存活中的作用。我们也会 确定CNTF诱导的代谢中涉及的细胞因子信号传导成分的不同功能 更改。拟议研究的结果将提高我们对神经保护机制的了解， 特别是代谢在维持神经元生存中的作用，从而促进了更多的发展 视网膜变性的有效治疗方法。