Molecular Genetics of Age-Dependent Retinal Degeneration

年龄依赖性视网膜变性的分子遗传学

• 批准号: 10657857
• 负责人: AKIHIRO IKEDA
• 金额: $ 49.51万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657857
• 关键词: Ablation; Abnormal Epithelial Cell; Acceleration; Acetyl-CoA Carboxylase; Affect; Age related macular degeneration; Aging; Binding; Cells; Choroid; Data; Development; Disease; Docosahexaenoic acid supplementation; Fatty Acids; Funding; Gene Expression; Genes; Genetic study; Health; Hepatic; Homeostasis; Impairment; Inflammation; Integral Membrane Protein; Lead; Liver; Mitochondria; Molecular Genetics; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Organelles; Pathology; Pathway interactions; Patients; Photoreceptors; Play; Prevention strategy; Process; Production; Regulation; Regulatory Element; Retina; Retinal Degeneration; Retinal Diseases; Role; Site; Sterols; Structure of retinal pigment epithelium; Supplementation; Testing; Therapeutic; Up-Regulation; age related; differential expression; disease phenotype; epidemiology study; fatty acid metabolism; functional loss; insight; lipid metabolism; lipidomics; mouse model; mutant; novel; overexpression; peroxisome; tool; transcription factor

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.

脂代谢紊乱与年龄依赖性视网膜密切相关 疾病包括年龄相关性黄斑变性(AMD)，基于遗传和 流行病学研究。然而，脂代谢失调在糖尿病的发生发展中的作用 与年龄相关的视网膜疾病的进展在很大程度上仍不清楚。小鼠模型 显示出视网膜中脂质代谢和细胞内稳态的损害提供了极好的 研究脂代谢失调如何影响视网膜健康并导致衰老的工具- 依赖型视网膜疾病。我们发现了一个这样的小鼠品系，它含有一种突变 跨膜蛋白135(Tmem135)，显示视网膜加速衰老的迹象，如 以及AMD的病理变化，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 在Tem135突变小鼠中，动力学是失调的。在上一个资助期，我们进一步 确定了TMEM135在视网膜脂代谢中的作用。我们的脂质组学数据显示 Tem135小鼠体内DHA水平降低，表明TMEM135在DHA输出中起作用 来自于过氧化物体。我们还发现TMEM135对过氧化物体的调节是至关重要的 视网膜的数量和脂类代谢。过氧化物体的数量与 Tem135突变小鼠和高表达小鼠线粒体的形态和功能 Tme135(Tmgm135 Tg)，表明这些细胞器之间存在密切的相互作用。此外， 小鼠脂肪代谢相关基因表达的改变 与AMD患者RPE/脉络膜差异表达基因相似的眼部。 基于这些发现，我们假设“通过调节过氧化体的功能 TMEM135对于维持RPE的正常功能和完整性至关重要 光感受器细胞，其失调导致年龄依赖性视网膜疾病的表型。 在这个更新方案中，我们将研究TMEM135如何调节脂代谢， 线粒体功能和视网膜功能通过其在过氧化体和DHA合成中的作用而发挥作用。 具体地说，我们将1)检验这样一种假设，即Tem135突变小鼠的DHA水平降低 是视网膜异常的原因，2)测定脂肪酸的贡献 Tmem135突变型视网膜病变的合成途径，以及3)检测过氧体的作用 在RPE的线粒体动态平衡中。该项目的成功完成将揭示 Tmem135在视网膜细胞增龄性变化中的作用未知，并确定 这些过程中涉及的因素，可能导致新的补充或治疗 视网膜中老化和与年龄相关的疾病的选择。

项目成果

The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease.

• DOI: 10.3390/cells10071593
• 发表时间: 2021-06-25
• 期刊: Cells
• 影响因子: 6
• 作者: Muench NA;Patel S;Maes ME;Donahue RJ;Ikeda A;Nickells RW
• 通讯作者: Nickells RW

Genetic basis of age-dependent synaptic abnormalities in the retina.

视网膜中年龄依赖性突触异常的遗传基础。

• DOI: 10.1007/s00335-014-9546-7
• 发表时间: 2015-02
• 期刊: MAMMALIAN GENOME
• 影响因子: 2.5
• 作者: Higuchi, Hitoshi;Macke, Erica L.;Lee, Wei-Hua;Miller, Sam A.;Xu, James C.;Ikeda, Sakae;Ikeda, Akihiro
• 通讯作者: Ikeda, Akihiro