Autophagy: A critical factor in RPE aging and AMD

视网膜相关性黄斑变性（AMD）是老年人视力损害的主要原因。 美国的老人。自噬是细胞管家的重要途径， 在受损细胞器移位至溶酶体进行降解中的作用。我们的数据 证实自噬在RPE管家中起关键作用， 效率随着年龄和AMD而下降。我们的结论是，有缺陷的自噬将 当受损细胞器的去除和修复不能 发生.因此，我们假设“RPE中自噬的减少在RPE中起主要作用， 在视网膜老化和老年性黄斑变性发病机制中的作用 （AMD）。我们进一步假设，减少自噬有助于 脂褐质的形成，通过降低自噬活性和 等待自噬降解的受损细胞内细胞器的积累 和替换。我们认为，刺激自噬途径， 反过来会导致累积的受损细胞器减少， 视网膜老化的变化和减缓AMD的进展，并导致识别 新的药理学靶点。“在目标1中，我们将描述空间和 人类和动物RPE中自噬途径的时间动力学， 这是如何随着年龄的增长和AMD的进展而变化的。在aim 2中，我们将使用primary a）表征氧化损伤对人RPE培养物的功效的作用， 自噬途径及其处理日益增加的受损细胞负担的能力 细胞内细胞器，B）RPE对氧化应激的敏感性， 自噬途径的下调和c）评估自噬途径的贡献 去除受损的细胞内细胞器以在RPE中形成脂褐素。在aim中 3，我们将评估修饰自噬对视网膜神经元损伤的体外和体内模型的影响。 老化和AMD。我们将确定那些最能抑制自噬的条件， 在体外产生AMD样病变，并将其转化为动物， 调节自噬途径的特定元件的表达水平或功能 可诱导野生型小鼠AMD样病变。最后，我们将确定是否增强 在两种小鼠模型中，自噬途径可以减缓AMD的进展。我们 认为RPE中自噬途径功能障碍的特征， AMD视网膜将确定治疗这种疾病的新靶点。

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 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.