Metabolism and neuronal viability of the retina

项目总结 视网膜营养不良导致的视力障碍严重影响了全球数百万人的生活质量- 很宽。尽管近几十年来取得了进展，但目前的药物仍然缺乏对许多人安全有效的治疗方法 致盲的疾病。旨在延缓神经元丢失和保护视觉功能的神经保护疗法 因此，对于治疗进展缓慢的失明疾病，如与年龄有关的疾病，这可能是一种有用的策略 黄斑变性和青光眼。细胞因子睫状神经营养因子(CNTF)被认为是一种 多种视网膜变性模型中的有效神经保护剂。然而，长期接触高剂量的 剂量的CNTF会导致视觉功能的抑制，尽管可以防止神经元死亡。为了 利用CNTF的好处同时避免CNTF的不利影响，了解CNTF信号至关重要- 在视网膜中诱导细胞事件。 为了更好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 我们设计的病毒载体感染小鼠视网膜变性模型的分子遗传学分析 表达与临床试验中使用的相同的人重组CNTF。我们证明了CNTF 最初的目标是穆勒胶质细胞，这反过来又激活了穆勒胶质细胞和光感受器之间的信号循环， 导致感光器存活。我们还表明，CNTF信号迅速而广泛地改变了 视网膜转录组，这可能是CNTF介导的视功能抑制的基础。此外，我们 已经证明，去除杆状感光细胞中的细胞因子信号抑制物足以增强 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的调节 可以促进光感受器的存活。此外，我们最近的研究表明，CNTF治疗 影响视网膜新陈代谢，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物化学方法来加深我们对 CNTF在视网膜中引发的细胞过程。我们将检查特定细胞类型的转录改变 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。我们会 评估一种关键的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诱导代谢的细胞因子信号成分的不同功能 改变。拟议的研究结果将促进我们对神经保护机制的了解， 尤其是新陈代谢在维持神经元存活方面的作用，从而促进更多 治疗视网膜变性的有效方法。

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.