Autophagy: A critical factor in RPE aging and AMD

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国老年人视力损害的主要原因。自噬是细胞管家的重要途径，在受损细胞器移位到溶酶体进行降解中起关键作用。我们的数据证实，自噬在RPE管家中起着关键作用，自噬效率随着年龄和AMD而下降。我们的结论是，有缺陷的自噬将损害正常的RPE功能时，损坏的细胞器的去除和修复不发生。因此，我们假设"RPE中自噬的减少在视网膜老化和年龄相关性黄斑变性（AMD）的发病机制中起着重要作用。我们进一步假设，减少自噬有助于脂褐质的发生，通过减少自噬活性和积累受损的细胞内细胞器等待自噬降解和更换的组合。我们认为，刺激自噬途径，这将反过来导致累积的受损细胞器的减少，将减少视网膜老化变化，减缓AMD的进展，并导致新的药理学靶点的鉴定。“在目标1中，我们将描述人类和动物RPE中自噬途径的时空动态，并确定其如何随着衰老和AMD的进展而变化。在目标2中，我们将使用原代人RPE培养物来a）表征氧化损伤对自噬途径的效率的作用及其处理受损细胞内细胞器的日益增加的负担的能力，B）在自噬途径上调或下调后RPE对氧化应激的敏感性，和评估自噬去除受损细胞内细胞器对RPE中脂褐质形成的贡献。在目标3中，我们将评估修饰自噬对视网膜老化和AMD的体外和体内模型的影响。我们将确定那些条件，最好地抑制自噬，并在体外产生AMD样病变，并将这些翻译到动物，并确定是否下调表达水平或自噬途径的特定元素的功能可以诱导野生型小鼠的AMD样病变。最后，我们将在两种小鼠模型中确定增强自噬通路是否可以减缓AMD的进展。我们相信，AMD视网膜RPE中自噬通路功能障碍的表征将确定治疗这种疾病的新靶点。公共卫生相关性：视网膜相关性黄斑变性（AMD）是老年人失明的主要原因，在美国有超过1000万人因AMD而视力下降。了解自噬的作用将为AMD的发病机制提供新的信息，并可能有助于制定可持续的治疗策略，特别是对于干性AMD，这是NEI的优先领域。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of visual impairment of the elderly in the US. Autophagy is a vital pathway in cellular housekeeping and plays a critical role in the translocation of damaged organelles to the lysosome for degradation. Our data confirm that autophagy plays a critical role in RPE housekeeping and that autophagic efficiency declines with both age and AMD. We conclude that defective autophagy will impair normal RPE function when removal and repair of damaged organelles does not occur. We therefore hypothesize that "Decreased autophagy in the RPE plays a major role in retinal aging and the pathogenesis of age-related macular degeneration (AMD). We further postulate that decreased autophagy contributes toward the genesis of lipofuscin, via a combination of reduced autophagic activity and an accumulation of damaged intracellular organelles awaiting autophagic degradation and replacement. We believe that stimulation of the autophagic pathway, which would in turn lead to a reduction in accumulated damaged organelles will reduce retinal aging changes and slow the progression of AMD and lead to the identification of new pharmacological targets." In aim 1, we will characterize the spatial and temporal dynamics of the autophagic pathway in human and animal RPE and determine how this changes with aging and the progression of AMD. In aim 2, we will use primary human RPE cultures to a) characterize the role of oxidative damage on the efficiency of the autophagic pathway and its ability to deal with an increasing burden of damaged intracellular organelles, b) the susceptibility of the RPE to oxidative stress following up or down regulation of the autophagic pathway and c) assess the contribution of autophagic removal of compromised intracellular organelles to lipofuscin formation in the RPE. In aim 3, we will assess the effect of modifying autophagy on in vitro and in vivo models of retinal aging and AMD. We will identify those conditions that best suppress autophagy and generate AMD-like lesions in vitro and translate these to animals and determine if down regulation of expression levels or function of specific elements of the autophagic pathways can induce the AMD-like lesions in wild type mice. Finally, we will determine if enhancing the autophagic pathway can slow the progression of AMD in two mouse models. We believe that characterization of dysfunction in the autophagic pathway in the RPE of AMD retinas will identify new targets in the treatment of this disease. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the major cause of blindness in the elderly, with over 10 million people having reduced vision due to AMD in the US. Understanding the role of autophagy will provide new information on the pathogenesis of AMD and may help develop a sustainable treatment strategy, especially for dry AMD, which is a priority area for the NEI.