Molecular Genetics of Age-Dependent Retinal Degeneration

脂质代谢失调与年龄依赖性视网膜病变密切相关 包括年龄相关性黄斑变性（AMD）在内的疾病， 流行病学研究。然而，脂质代谢失调在发育中的作用， 和年龄依赖性视网膜疾病的进展仍然是未知的。小鼠模型 显示视网膜中脂质代谢和细胞内稳态的损伤提供了极好的 研究脂质代谢失调如何影响视网膜健康并导致衰老的工具- 依赖性视网膜疾病我们发现了一个这样的小鼠品系， 跨膜蛋白135（Tmem 135），显示视网膜加速老化的迹象， 以及在AMD中观察到的病理学，包括视网膜色素上皮（RPE）细胞 异常、炎症和感光细胞变性。我们发现线粒体 动力学在Tmem 135突变小鼠中失调。在上一个融资期，我们进一步 鉴定了TMEM 135在视网膜脂质代谢中的作用。我们的脂质组学数据显示 降低TMEM 135小鼠中的DHA水平，并表明TMEM 135在DHA输出中起作用 来自过氧化物酶体我们还发现TMEM 135对过氧化物酶体的调节至关重要， 视网膜中的数量和脂质代谢。过氧化物酶体的数量与 Tmem 135突变小鼠和Tmem 135过表达小鼠的线粒体形态和功能 Tmem 135（Tmgm 135 TG），表明这些细胞器之间的密切相互作用。此外，委员会认为， Tmem 135突变改变小鼠脂质代谢相关基因表达 眼杯，其与AMD患者的RPE/脉络膜中差异表达的基因相似。 基于这些发现，我们假设“通过以下方式调节过氧化物酶体功能 TMEM 135对于维持RPE的正常功能和完整性至关重要， 感光细胞，其失调导致年龄依赖性视网膜疾病表型。 在这项更新提案中，我们将研究TMEM 135如何调节脂质代谢， 通过其在过氧化物酶体和DHA合成中的作用来实现线粒体功能和视网膜功能。 具体来说，我们将1）测试Tmem 135突变小鼠中DHA水平降低的假设， 负责视网膜异常，2）确定脂肪酸的贡献 合成途径对Tmem 135突变体视网膜病变的影响，以及3）测试过氧化物酶体的作用 在视网膜色素上皮的线粒体内稳态中起着重要作用。该项目的成功完成将揭示 Tmem 135在视网膜细胞年龄依赖性变化中的作用， 参与这些过程的因素，这可能导致新的补充或治疗 视网膜老化和与年龄有关的疾病的选择。

Dysregulation of lipid metabolism is strongly associated with age-dependent retinal diseases including age-related macular degeneration (AMD) based on genetic and epidemiological studies. However, the roles of dysregulated lipid metabolism in the development and progression of age-dependent retinal diseases remain largely unknown. Mouse models showing impairment of lipid metabolism and cellular homeostasis in the retina provide excellent tools to study how dysregulated lipid metabolism impacts retinal health and lead to age- dependent retinal diseases. We identified one such mouse strain harboring a mutation in transmembrane protein 135 (Tmem135) that displays signs of accelerated aging in the retina as well as pathologies observed in AMD including retinal pigment epithelium (RPE) cell abnormalities, inflammation and photoreceptor cell degeneration. We found that mitochondrial dynamics are dysregulated in Tmem135 mutant mice. In the previous funding period, we further identified the role of TMEM135 in lipid metabolism in the retina. Our lipidomics data showed reduced DHA levels in Tmem135 mice and indicated that TMEM135 has a role in DHA export from peroxisomes. We also found that TMEM135 is critical for the regulation of peroxisomal number and lipid metabolism in the retina. The number of peroxisomes is correlated with mitochondrial morphology and function in Tmem135 mutant mice and mice overexpressing Tmem135 (Tmgm135 TG), suggesting close interaction between these organelles. Moreover, the Tmem135 mutation changes expression of genes associated with lipid metabolism in mouse eyecups, which are similar to genes differentially expressed in RPE/choroid of AMD patients. Based on these findings, we hypothesize that “Regulation of peroxisomal functions through TMEM135 is essential to maintaining the normal function and integrity of RPE and photoreceptor cells, dysregulation of which leads to age-dependent retinal disease phenotypes.” In this renewal proposal, we will investigate how TMEM135 regulates lipid metabolism, mitochondrial function and retinal function through its role in peroxisomes and DHA synthesis. Specifically, we will 1) test the hypothesis that decreased DHA levels in Tmem135 mutant mice are responsible for the retinal abnormalities, 2) determine the contributions of fatty acid synthesis pathways on Tmem135 mutant retinal pathologies, and 3) test the role of peroxisomes in mitochondrial homeostasis in the RPE. Successful completion of this project will reveal the previously unknown role of Tmem135 in age-dependent changes of retinal 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.