Molecular Genetics of Age-Dependent Retinal Degeneration

年龄依赖性视网膜变性的分子遗传学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我们的长期目标是了解导致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加速衰老过程环境和遗传因素。我们之前的研究表明，小鼠模型显示加速衰老表型是识别视网膜中此类因素的有力工具。 ENU诱导的突变小鼠模型， FUN025，显示视网膜加速老化，以及在与年龄相关的视网膜中观察到的某些关键病理疾病包括视网膜色素上皮 (RPE) 细胞异常、炎症和感光细胞变性，表明该负责基因参与视网膜衰老的调节，并且其损害会导致年龄依赖性视网膜异常的发生。在上一个资助期内，我们发现跨膜蛋白 135 (Tmem135) 的突变导致视网膜 FUN025 小鼠的异常。我们发现 TMEM135 定位于线粒体，并参与线粒体裂变。培养的 Tmem135 突变细胞和突变体对氧化应激的敏感性增加视网膜，可能是由于线粒体异常。我们的观察表明 RPE 是主要部位受 Tmem135 突变的影响。此外，我们发现野生型Tmem135在小鼠体内过度表达导致 RPE 细胞变性。基于这些发现，我们假设线粒体的适当控制 TMEM135 的动态对于维持 RPE 细胞的正常功能和完整性、失调至关重要这会导致年龄依赖性异常。除了我们自己的发现之外，还有越来越多的证据表明表明 RPE 是年龄依赖性疾病（包括年龄相关性黄斑变性）的目标。然而，这些与年龄相关的疾病中 RPE 功能障碍/死亡的病因尚不清楚。在这次更新中提议，我们将研究 Tmem135 导致的线粒体动力学缺陷如何导致 RPE 功能障碍/退化。具体来说，我们将 1) 确定受 Tmem135 影响的分子途径 RPE 细胞中的突变/过度表达，2) 研究线粒体动力学如何影响线粒体的完整性和功能 RPE 以及 TMEM135 如何参与此过程，以及 3) 识别 RPE 细胞的遗传修饰因子 Tmem135 过度表达引起的退化。该项目的成功完成将揭示 RPE 细胞年龄依赖性变化中的线粒体动力学和 Tmem135，并确定参与的因素这些过程可能会导致针对衰老和年龄相关的新的补充或治疗选择视网膜疾病。