The Function of Transmembrane Protein 135 in Retinal Pigmented Epithelium

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患上视网膜疾病 病理学仍然是一个悬而未决的问题。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加速衰老的关键遗传因素。vbl.使用 该方法被鉴定为跨膜蛋白135(Tem135)，是一个与视网膜衰老有关的重要基因。 TMem135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， 线粒体为保持其结构和功能而经历的集体过程。我们假设这是恰当的 通过TMEM135控制线粒体动力学对于维持正常的视网膜功能是必不可少的。 它的失调会导致加速老化的视网膜病理。然而，机制是如何 Tme135调节线粒体动力学，视网膜衰老尚不清楚。在这个提案中，我们探讨了 在视网膜色素上皮(RPE)细胞中表达。Tem135中的RPE细胞较厚、致密且较小 突变的小鼠，而RPE细胞在过度表达野生型的小鼠中畸形和退化 Tem135与各自的对照进行比较。这些RPE变化对应于相对的线粒体 这些基因型别的形态。这些初步数据表明，RPE细胞及其线粒体是 对TMEM135的变化敏感。这项培训拨款提案的主要目标是学习和使用鼠标 基因技术，以确定TMEM135如何维持RPE和线粒体动态平衡。这个 TMEM135在RPE细胞中的功能将通过两个目的利用小鼠遗传学技术进行研究。 在目标1中，我们将识别和验证修改Tmem135诱导的RPE表型的候选基因 过度表达。在目标2中，我们将研究TMEM135与丙二酰辅酶A的关系 (丙二酰辅酶A)途径。综上所述，这一建议将加深我们对TMEM135在眼睛中的功能的理解 以及衰老在视网膜疾病发展中的作用。

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.