Metabolism and neuronal viability of the retina

项目摘要 视网膜营养不良引起的视力障碍严重影响世界上数百万人的生活质量- 宽尽管近几十年来取得了进展，但目前的医学仍然缺乏安全有效的治疗方法， 致盲疾病神经保护疗法旨在延缓神经元丧失和保护视觉功能 因此，这可能是治疗缓慢进展的致盲性疾病（如年龄相关性疾病）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）是已知的作为 在各种视网膜变性模型中的有效神经保护剂。然而，长期接触高浓度的 剂量的CNTF导致视觉功能的抑制，尽管防止了神经元死亡。为了 利用CNTF的有益作用，同时避免其有害作用，了解CNTF信号至关重要- 在视网膜中引发细胞事件。 为了更深入地了解正在进行的旨在治疗致盲性疾病的CNTF临床试验，我们进行了 用我们设计的病毒载体感染的小鼠视网膜变性模型的分子遗传学分析 表达临床试验中使用的相同的人重组CNTF。我们证明CNTF 最初靶向Muller神经胶质，这反过来激活Muller神经胶质和光感受器之间的信号回路， 导致感光细胞存活。我们还发现，CNTF信号传导迅速而广泛地改变了 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，去除视杆细胞光感受器中的细胞因子信号传导抑制剂足以增强 它们在缺乏外源性CNTF的情况下存活，表明内源性细胞因子信号传导的调节 可促进感光细胞活力。此外，我们最近的研究表明，CNTF治疗深刻地 影响视网膜的新陈代谢，导致有氧糖酵解增强， 生产，并恢复视网膜氧化还原状态。 拟议的研究将联合收割机结合分子和生物化学方法，以进一步了解 CNTF在视网膜中引起的细胞过程。我们将研究细胞类型特异性转录组学变化 和改变的代谢途径，以充分评估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。我们还将 确定参与CNTF诱导的代谢的细胞因子信号传导组分的不同功能， 变化这项研究的结果将促进我们对神经保护机制的了解， 特别是代谢在维持神经元存活中的作用，从而促进更多的神经元的发育。 视网膜变性的有效治疗。

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.