Autophagy: A critical factor in RPE aging and AMD

自噬：R​​PE 老化和 AMD 的关键因素

• 批准号: 8698871
• 负责人: Michael Edwin Boulton
• 金额: $ 2.67万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698871
• 关键词: Autophagy; critical; factor; RPE; aging

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.

与年龄有关的黄斑变性（AMD）是视觉障碍的主要原因 在美国的老年人。自噬是蜂窝管家中的重要途径，并且发挥着关键的作用 在受损细胞器转移到溶酶体降解中的作用。我们的数据 确认自噬在RPE管家中起着至关重要的作用 年龄和AMD的效率下降。我们得出结论，有缺陷的自噬将 删除和修复受损细胞器的正常RPE功能不会 发生。因此，我们假设“ RPE中的自噬减少起作用 在视网膜老化和年龄相关黄斑变性的发病机理中的作用 （AMD）。我们进一步指出，自噬减少有助于 脂肪霉素的起源，通过降低的自噬活性和A的结合 等待自噬降解的细胞内细胞器的累积 和更换。我们认为，刺激自噬途径 反过 视网膜老化变化并减慢AMD的进展并导致识别 在AIM 1中，我们将表征空间和 人和动物RPE自噬途径的时间动力学并确定 这如何随老化和AMD的进展而变化。在AIM 2中，我们将使用主要 人类RPE培养物a）表征氧化损伤对效率的作用 自噬途径及其应对越来越受损负担的能力 细胞内细胞器，b）RPE对后续氧化应激的敏感性或 下调自噬途径和c）评估自噬的贡献 将受损的细胞内细胞器去除RPE中的脂肪霉素形成。目标 3，我们将评估修饰自噬对视网膜体外和体内模型的影响 衰老和AMD。我们将确定那些最能抑制自噬和的条件 在体外产生类似AMD的病变，并将其转化为动物，并确定是否向下 调节自噬途径的特定元素的表达水平或功能 可以在野生型小鼠中诱导类似AMD的病变。最后，我们将确定是否增强 自噬途径可以减慢两个小鼠模型中AMD的进展。我们 相信在RPE自噬途径中功能障碍的表征 AMD视网膜将确定治疗该疾病的新目标。

项目成果

Autophagy in the retina: a potential role in age-related macular degeneration.

• DOI: 10.1007/978-1-4614-0631-0_12
• 发表时间: 2012
• 期刊: ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
• 作者: Mitter, Sayak K.;Rao, Haripriya Vittal;Qi, Xiaoping;Cai, Jun;Sugrue, Andrew;Dunn, William A., Jr.;Grant, Maria B.;Boulton, Michael E.
• 通讯作者: Boulton, Michael E.

Concentration dependence of vitamin C in combinations with vitamin E and zeaxanthin on light-induced toxicity to retinal pigment epithelial cells.

• DOI: 10.1111/j.1751-1097.2012.01228.x
• 发表时间: 2012-11
• 期刊: Photochemistry and photobiology
• 影响因子: 3.3
• 作者: Różanowska M;Bakker L;Boulton ME;Różanowski B
• 通讯作者: Różanowski B

Studying melanin and lipofuscin in RPE cell culture models.

• DOI: 10.1016/j.exer.2014.01.016
• 发表时间: 2014-09
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Boulton, Michael E.

The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.

• DOI: 10.1371/journal.pone.0034468
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Thampi P;Rao HV;Mitter SK;Cai J;Mao H;Li H;Seo S;Qi X;Lewin AS;Romano C;Boulton ME
• 通讯作者: Boulton ME

Proteomic profiling of human retinal pigment epithelium exposed to an advanced glycation-modified substrate.

• DOI: 10.1007/s00417-011-1856-9
• 发表时间: 2012-03
• 期刊: GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
• 影响因子: 2.7
• 作者: Glenn, J. V.;Mahaffy, H.;Dasari, S.;Oliver, M.;Chen, M.;Boulton, M. E.;Xu, H.;Curry, W. J.;Stitt, Alan W.
• 通讯作者: Stitt, Alan W.