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

研究线粒体稳态作为年龄相关性黄斑变性的病理机制

• 批准号: 10367942
• 负责人: Cody R Fisher
• 金额: $ 1.07万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10367942
• 关键词: 3-Dimensional; Affect; Age; Age related macular degeneration; Atrophic; Autophagocytosis; Bioenergetics; Biogenesis; Blindness; Cell Death; Cells; Cessation of life; Characteristics; Chemicals; Code; Cytoplasm; Data; Defect; Disease; Essential Genes; Failure; Financial Hardship; Fluorescent Probes; Functional disorder; Gene Expression; Gene Proteins; Genes; Green Fluorescent Proteins; Homeostasis; Human; Image Analysis; Inflammation; Kinetics; Lead; Lysosomes; Measurement; Measures; Microscopy; Mitochondria; Molecular; Nonexudative age-related macular degeneration; Oxygen Consumption; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Photoreceptors; Plasmids; Population; Process; Proteins; Quality of life; Recovery; Role; Site; Stress; Structure of retinal pigment epithelium; System; Testing; Time; Tissues; Western World; base; combinatorial; effective therapy; fluorophore; high resolution imaging; inhibitor; insight; microscopic imaging; mitochondrial autophagy; mitochondrial dysfunction; prevent; protein expression; reconstruction; repaired; stem; targeted treatment; therapeutic target

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.

项目摘要 与年龄有关的黄斑变性（AMD）是西方世界失明的主要原因， 增加了整个人口的财务负担。 AMD的干燥形式的特征是死亡 视网膜色素上皮（RPE）。许多研究都暗示线粒体功能障碍是潜在的 AMD病理的一部分。线粒体损伤和功能障碍在RPE组织和原发性 来自AMD的人类捐助者的RPE文化。由于线粒体功能障碍引起的生物能危机可能导致 与AMD相关的多种表型，包括炎症和细胞死亡。线粒体稳态， 包括生物发生，融合，裂变和线粒体自噬（线粒体）是疗法的主要靶标。 但是，导致功能失调和线粒体在AMD中损坏的途径不是 已知。这三个特定目的将评估线粒体生物发生，融合和裂变（AIM 1），线粒体。 （AIM 2）和潜在的分子机制（AIM 3）主要使用线粒体靶向荧光探针 测量这些动态过程。药理学激活剂或抑制剂将用于评估效果 线粒体稳态的线粒体功能。初步数据支持使用不同的可行性 线粒体靶向荧光蛋白测量线粒体稳态。确定步骤 线粒体稳态负责累积线粒体的积累将提供治疗性 治疗AMD的目标。