The Function of Transmembrane Protein 135 in Retinal Pigmented Epithelium

跨膜蛋白135在视网膜色素上皮中的功能

• 批准号: 10231869
• 负责人: Michael Landowski
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231869
• 关键词: Ablation; Acetyl-CoA Carboxylase; Affect; Age related macular degeneration; Aging; Alleles; Applications Grants; Blindness; Candidate Disease Gene; Choroid; Critical Pathways; Data; Development; Diabetic Retinopathy; Disease; Equilibrium; Ethylnitrosourea; Eye; Fatty Acids; Future; Gene-Modified; Genes; Genetic; Genetic Techniques; Genotype; Glaucoma; Goals; Health; Homeostasis; In Vitro; Integral Membrane Protein; Lead; Learning; Link; Malonyl Coenzyme A; Maps; Methods; Mitochondria; Morphology; Mus; Mutant Strains Mice; Mutation; Pathology; Pathway interactions; Phenotype; Prevalence; Process; Proteins; Resolution; Retina; Retinal Diseases; Risk Factors; Role; Sclera; Structure; Structure of retinal pigment epithelium; Testing; Therapeutic; Thick; Training; age related; congenic; fatty acid oxidation; forward genetics; in vivo; inhibitor/antagonist; mouse genetics; mutant; novel therapeutics; overexpression; positional cloning; preservation; prevent; transcriptome; transcriptomics

Project Abstract Aging is a significant risk factor for retinal disease development but how aging predisposes an eye to pathologies remains an unanswered question. One method to understand the role of aging in retinal disease development is to identify key genetic factors that lead to accelerated aging retinal phenotypes in mice. Using this method, transmembrane protein 135 (Tmem135) was identified as a gene important in retinal aging. Tmem135 encodes a protein that can colocalize with mitochondria and regulate mitochondrial dynamics, the collective process mitochondria undergo to preserve their structure and function. We hypothesize that proper control of mitochondrial dynamics through TMEM135 is essential to maintain normal retinal function, dysregulation of which leads to accelerated aging retinal pathologies. However, the mechanism of how Tmem135 regulates mitochondrial dynamics and retinal aging is unknown. In this proposal, we explore the role of Tmem135 in retinal pigmented epithelium (RPE) cells. RPE cells are thick, dense and small in Tmem135 mutant mice, whereas RPE cells are dysmorphogenic and degenerative in mice overexpressing wild-type Tmem135 compared to their respective controls. These RPE changes correspond to opposing mitochondria morphologies in these genotypes. These preliminary data indicate that RPE cells and their mitochondria are sensitive to changes in TMEM135. The main goal of this training grant proposal is to learn and utilize mouse genetic techniques in order to identify how TMEM135 maintains RPE and mitochondrial homeostasis. The function of TMEM135 within RPE cells will be investigated using mouse genetic techniques through two aims. In Aim 1, we will identify and validate candidate genes that modify the RPE phenotype induced by Tmem135 overexpression. In Aim 2, we will examine the relationship between TMEM135 and the malonyl-coenzyme A (malonyl-CoA) pathway. Together, this proposal will further our understanding of TMEM135 function in the eye and the role of aging in retinal disease development.

项目摘要 衰老是视网膜疾病发展的重要危险因素，但衰老如何使人眼中 病理仍然是一个未解决的问题。一种了解衰老在视网膜疾病中的作用的方法 发展是为了确定导致小鼠衰老的视网膜表型加速的关键遗传因素。使用 这种方法，跨膜蛋白135（TMEM135）被鉴定为在视网膜衰老中重要的基因。 TMEM135编码可以与线粒体共定位并调节线粒体动力学的蛋白质 集体过程线粒体会经历其结构和功能。我们假设这是正确的 通过TMEM135控制线粒体动力学对于维持正常视网膜功能至关重要， 失调导致衰老的视网膜病理加速。但是，如何 TMEM135调节线粒体动力学，视网膜衰老尚不清楚。在此提案中，我们探讨了角色 视网膜色素上皮（RPE）细胞中的TMEM135。 RPE细胞在TMEM135中厚，密集且小 突变小鼠，而RPE细胞在过表达野生型的小鼠中具有畸形和退化性 TMEM135与它们各自的对照相比。这些RPE变化对应于相反的线粒体 这些基因型中的形态。这些初步数据表明RPE细胞及其线粒体是 对TMEM135的变化敏感。该培训赠款建议的主要目标是学习和利用鼠标 遗传技术是为了确定TMEM135如何维持RPE和线粒体稳态。这 TMEM135在RPE细胞中的功能将通过小鼠遗传技术通过两个目标研究。 在AIM 1中，我们将识别和验证修改TMEM135诱导的RPE表型的候选基因 过表达。在AIM 2中，我们将研究TMEM135和丙二酰辅酶A之间的关系 （malonyl-COA）途径。这项建议将进一步了解我们对TMEM135功能的理解 以及衰老在视网膜疾病发展中的作用。