Molecular Genetics of Age-Dependent Retinal Degeneration

年龄依赖性视网膜变性的分子遗传学

• 批准号: 10459299
• 负责人: AKIHIRO IKEDA
• 金额: $ 52.09万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459299
• 关键词: ADP ribosylation; Ablation; Abnormal Epithelial Cell; Acceleration; Affect; Age related macular degeneration; Aging; Candidate Disease Gene; Cells; Cessation of life; Consumption; Defect; Development; Disease; Dynamin; Ethylnitrosourea; Etiology; Functional disorder; Funding; Genes; Genetic; Goals; Impairment; In Vitro; Inflammation; Integral Membrane Protein; Lead; Maps; Metabolic; Metabolic Pathway; Mitochondria; Molecular; Molecular Genetics; Mus; Mutation; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Phenotype; Photoreceptors; Play; Poly(ADP-ribose) Polymerases; Prevention strategy; Process; Proteins; Reaction; Regulation; Resolution; Retina; Retinal Degeneration; Retinal Diseases; Role; Severities; Site; Structure of retinal pigment epithelium; Supplementation; System; Testing; Therapeutic; age related; base; disease phenotype; human disease; in vivo; insight; metabolomics; mitochondrial DNA mutation; mouse model; mutant; mutant mouse model; novel; overexpression; tool

Project Summary Our long-term goal is to understand the molecular mechanisms causing human diseases associated with aging. One possible mechanism for age-dependent diseases is acceleration of the aging process by environmental and genetic factors. Our previous studies show that mouse models showing accelerated aging phenotypes are powerful tools to identify such factors in the retina. An ENU-induced mutant mouse model, FUN025, displays accelerated retinal aging, as well as certain key pathologies observed in age-related retinal diseases including retinal pigment epithelium (RPE) cell abnormalities, inflammation and photoreceptor cell degeneration, suggesting that the responsible gene is involved in the regulation of retinal aging, and that its impairment leads to development of the age-dependent retinal abnormalities. In the previous funding period, we identified that a mutation in transmembrane protein 135 (Tmem135) is responsible for the retinal abnormalities in FUN025 mice. We found that TMEM135 localizes to mitochondria, and is involved in mitochondrial fission. Sensitivity to oxidative stress increases in cultured Tmem135 mutant cells and mutant retina, likely due to the mitochondrial abnormalities. Our observations indicate that the RPE is the primary site affected by the Tmem135 mutation. In addition, we found that over-expression of wild-type Tmem135 in mice results in RPE cell degeneration. Based on these findings, we hypothesize that proper control of mitochondrial dynamics through TMEM135 is essential to maintain normal function and integrity of RPE cells, dysregulation of which leads to age-dependent abnormalities. In addition to our own findings, there is increasing evidence to show that RPE is the target of age-dependent diseases including age-related macular degeneration. However, the etiology of RPE dysfunction/death in these age-related diseases is not well understood. In this renewal proposal, we will investigate how defective mitochondrial dynamics due to Tmem135 result in RPE dysfunction/degeneration. Specifically, we will 1) determine molecular pathways affected by Tmem135 mutation/over-expression in RPE cells, 2) study how mitochondrial dynamics affect the integrity and function of the RPE and how TMEM135 is involved in this process, and 3) identify genetic modifiers of RPE cell degeneration caused by Tmem135 overexpression. Successful completion of this project will reveal the role of mitochondrial dynamics and Tmem135 in age-dependent changes of RPE cells, and identify factors involved in those processes, which may lead to novel supplementation or treatment options for aging and age-related diseases in the retina.

项目摘要 我们的长期目标是了解引起与人类疾病相关的人类疾病的分子机制 老化。年龄依赖性疾病的一种可能机制是通过 环境和遗传因素。我们以前的研究表明，鼠标模型显示出加速衰老 表型是在视网膜中识别此类因素的强大工具。 ENU诱导的突变小鼠模型， FUN025，显示加速的视网膜老化以及与年龄相关的视网膜中观察到的某些关键病理 包括视网膜色素上皮（RPE）细胞异常，炎症和感光细胞的疾病 变性，表明负责基因参与视网膜衰老的调节，并且 损伤导致年龄依赖性视网膜异常的发展。在上一个资金期间， 我们确定了跨膜蛋白135（TMEM135）中的突变是视网膜的 Fun025小鼠的异常。我们发现TMEM135本地化到线粒体，并参与 线粒体裂变。对氧化应激的敏感性增加了培养的TMEM135突变细胞和突变体的敏感性 视网膜，可能是由于线粒体异常。我们的观察结果表明RPE是主要部位 受TMEM135突变的影响。此外，我们发现小鼠野生型TMEM135的过表达 导致RPE细胞变性。基于这些发现，我们假设正确控制线粒体 通过TMEM135的动力学对于维持RPE细胞的正常功能和完整性，失调至关重要 其中导致年龄依赖性异常。除了我们自己的发现外，还有越来越多的证据 表明RPE是年龄依赖性疾病的靶标，包括与年龄相关的黄斑变性。然而， 这些与年龄有关的疾病中RPE功能障碍/死亡的病因尚不清楚。在此续约中 提案，我们将研究由于TMEM135引起的线粒体动力学有缺陷导致RPE 功能障碍/变性。具体而言，我们将1）确定受TMEM135影响的分子途径 RPE细胞中的突变/过表达，2）研究线粒体动力学如何影响 RPE和TMEM135如何参与此过程，3）识别RPE细胞的遗传修饰符 TMEM135过表达引起的变性。成功完成该项目将揭示 线粒体动力学和TMEM135在RPE细胞的年龄依赖性变化中，并确定涉及的因素 这些过程可能导致新颖的补充或与年龄相关的治疗选择 视网膜中的疾病。