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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要年龄相关性黄斑变性（AMD）是西方世界导致失明的主要原因，增加全体人民的经济负担。干性 AMD 的特点是细胞死亡视网膜色素上皮（RPE）。许多研究表明线粒体功能障碍是潜在的 AMD 病理学的一部分。 RPE 组织和原代细胞中均发现线粒体损伤和功能障碍。来自患有 AMD 的人类捐赠者的 RPE 培养物。线粒体功能障碍导致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（mitophagy），是治疗的主要目标。然而，导致 AMD 中功能失调和受损线粒体积累的途径却并非如此。已知。这三个具体目标将评估线粒体生物发生、融合和裂变（目标 1）、线粒体自噬（目标 2）和主要使用线粒体靶向荧光探针的潜在分子机制（目标 3）来测量这些动态过程。将使用药理学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来测量线粒体稳态。识别步骤负责受损线粒体积累的线粒体稳态将提供治疗作用治疗 AMD 的目标。