Metabolism and neuronal viability of the retina

视网膜的新陈代谢和神经元活力

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要视网膜营养不良引起的视力障碍严重影响世界数百万人的生活质量宽的。尽管近几十年来取得了进步，但当前的医学仍然缺乏针对许多疾病的安全有效的治疗方法致盲疾病。旨在延缓神经元损失和保留视觉功能的神经保护疗法因此，可能是治疗缓慢进展的致盲疾病（例如与年龄相关的疾病）的有用策略。黄斑变性和青光眼。已知细胞因子睫状神经营养因子 (CNTF) 在多种视网膜变性模型中有效的神经保护剂。然而，长期暴露于高尽管可以防止神经元死亡，但一定剂量的 CNTF 仍会导致视觉功能受到抑制。为了利用 CNTF 的益处同时避免其不利影响，了解 CNTF 信号至关重要- 诱导视网膜细胞事件。为了更深入地了解正在进行的旨在治疗致盲疾病的 CNTF 临床试验，我们进行了对感染我们设计的病毒载体的小鼠视网膜变性模型进行分子遗传学分析表达与临床试验中使用的相同的人类重组 CNTF。我们证明了 CNTF 最初以穆勒神经胶质细胞为目标，后者反过来激活穆勒神经胶质细胞和光感受器之间的信号环路，导致光感受器存活。我们还表明 CNTF 信号传导能够快速而广泛地改变视网膜转录组，这可能是 CNTF 介导的视觉功能抑制的基础。此外，我们已经证明去除视杆光感受器中的细胞因子信号传导抑制剂足以增强它们在没有外源性 CNTF 的情况下存活，表明内源性细胞因子信号传导的调节可以促进光感受器的活力。此外，我们最近的研究表明 CNTF 治疗对影响视网膜代谢，导致有氧糖酵解和合成代谢增强，能量增加生产，并恢复视网膜氧化还原状态。拟议的研究将结合分子和生化方法来进一步加深我们对 CNTF 在视网膜中引发的细胞过程。我们将检查细胞类型特异性转录组变化并改变代谢途径，以全面评估 CNTF 治疗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。我们也会确定参与 CNTF 诱导代谢的细胞因子信号传导成分的独特功能变化。拟议研究的结果将增进我们对神经保护机制的了解，特别是新陈代谢在维持神经元存活中的作用，从而促进更多的发育有效治疗视网膜变性。