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一个重要风险因素，但衰老如何使眼睛容易发生视网膜病变？ 病理学仍然是一个没有答案的问题。了解衰老在视网膜疾病中的作用的一种方法 开发的目的是确定导致小鼠视网膜表型加速老化的关键遗传因素。使用 该方法，跨膜蛋白135（Tmem 135）被鉴定为在视网膜老化中重要的基因。 TMEM 135编码一种可以与线粒体共定位并调节线粒体动力学的蛋白质， 线粒体为了保持其结构和功能而经历的集体过程。我们假设 通过TMEM 135控制线粒体动力学对于维持正常视网膜功能是必不可少的， 其失调导致加速老化的视网膜病变。然而， Tmem 135调节线粒体动力学和视网膜老化是未知的。在本建议中，我们探讨了 Tmem 135在视网膜色素上皮细胞中的表达。Tmem 135中的RPE细胞厚、密、小 突变小鼠，而RPE细胞是畸形和变性的小鼠过度表达野生型 Tmem 135与其各自的对照相比。这些RPE变化对应于对立的线粒体 这些基因型的形态。这些初步数据表明，RPE细胞及其线粒体是 对TMEM 135的变化敏感。这项培训补助金提案的主要目标是学习和利用鼠标 基因技术，以确定TMEM 135如何维持RPE和线粒体稳态。的 将通过两个目的使用小鼠遗传技术研究TMEM 135在RPE细胞内的功能。 在目标1中，我们将鉴定和验证修饰Tmem 135诱导的RPE表型的候选基因。 过度表达在目的2中，我们将研究TMEM 135和丙二酰辅酶A之间的关系。 （丙二酰-CoA）途径。总之，这项提议将进一步加深我们对TMEM 135在眼睛中功能的理解。 以及老化在视网膜疾病发展中的作用。