The Function of Transmembrane Protein 135 in Retinal Pigmented Epithelium

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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.