Investigating Mitochodrial Homeostasis as a Pathological Mechanism of Age Related Macular Degeneration

项目摘要 老年性黄斑变性(AMD)是西方世界导致失明的主要原因， 增加了整个人口的经济负担。干性AMD的特征是 视网膜色素上皮(RPE)。大量研究表明线粒体功能障碍是一种潜在的 是AMD病理的一部分。在RPE组织和原发性RPE中都发现了线粒体损伤和功能障碍 来自AMD患者捐献者的RPE培养。线粒体功能障碍引起的生物能量危机可能会导致 与AMD相关的多种表型，包括炎症和细胞死亡。线粒体动态平衡， 包括生物发生、融合、分裂和线粒体自噬(有丝分裂)，是治疗的主要靶点。 然而，导致AMD患者功能障碍和受损线粒体积累的途径并不是 为人所知。这三个具体目标将评估线粒体的生物发生、融合和分裂(目标1)、有丝分裂 (目标2)和可能的分子机制(目标3)，主要使用线粒体靶向荧光探针 来测量这些动态过程。将使用药理激活剂或抑制剂来评估效果。 线粒体稳态对线粒体功能的影响。初步数据支持使用不同方法的可行性 线粒体靶向荧光蛋白测量线粒体内稳态。确定以下步骤 导致受损线粒体积累的线粒体动态平衡将提供治疗 治疗AMD的靶点。

Project Summary Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world, with an increasing financial burden on the entire population. The dry form of AMD is characterized by the death of the retinal pigment epithelium (RPE). Numerous studies have implicated mitochondrial dysfunction as a potential part of AMD pathology. Mitochondrial damage and dysfunction have been found in both RPE tissue and primary RPE cultures from human donors with AMD. A bioenergetic crisis due to mitochondrial dysfunction could lead to the multiple phenotypes associated with AMD, including inflammation and cell death. Mitochondrial homeostasis, including biogenesis, fusion, fission, and mitochondrial autophagy (mitophagy), is a prime target for therapies. However the pathway that leads to the accumulation of dysfunctional and damaged mitochondria in AMD is not known. The three specific aims will assess mitochondrial biogenesis, fusion, and fission (Aim 1), mitophagy (Aim 2), and potential molecular mechanisms (Aim 3) primarily using mitochondrial-targeted fluorescent probes to measure these dynamic processes. Pharmacological activators or inhibitors will be used to assess the effect of mitochondrial homeostasis on mitochondrial function. Preliminary data support the feasibility of using different mitochondrial targeted fluorescent proteins to measure mitochondrial homeostasis. Identifying the step of mitochondrial homeostasis responsible for accumulation of damaged mitochondria will provide therapeutic targets to treat AMD.