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.

脂质代谢失调与年龄依赖性视网膜密切相关 疾病，包括基于遗传和年龄相关性黄斑变性（AMD） 然而，脂质代谢失调在发育中的作用。 年龄依赖性视网膜疾病的进展仍然很大程度上未知。 显示视网膜脂质代谢和细胞稳态受损提供了极好的 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 我们发现了一种携带突变的小鼠品系。 跨膜蛋白 135 (Tmem135) 在视网膜中表现出加速衰老的迹象 以及 AMD 中观察到的病理，包括视网膜色素上皮 (RPE) 细胞 我们发现线粒体异常、炎症和感光细胞变性。 在之前的资助期间，我们进一步研究了 Tmem135 突变小鼠的动力学失调。 我们的脂质组学数据显示，确定了 TMEM135 在视网膜脂质代谢中的作用。 降低 Tmem135 小鼠的 DHA 水平，表明 TMEM135 在 DHA 输出中发挥作用 我们还发现 TMEM135 对于过氧化物酶体的调节至关重要。 视网膜中过氧化物酶体的数量与脂质代谢相关。 Tmem135突变小鼠和过表达小鼠的线粒体形态和功能 Tmem135 (Tmgm135 TG)，表明这些细胞器之间存在密切的相互作用。 Tmem135突变改变了小鼠脂质代谢相关基因的表达 眼罩，与 AMD 患者 RPE/脉络膜差异表达的基因相似。 基于这些发现，我们努力“通过调节过氧化物酶体功能” TMEM135 对于维持 RPE 和 RPE 的正常功能和完整性至关重要 感光细胞，其失调会导致年龄依赖性视网膜疾病表型。” 在这个更新提案中，我们将研究TMEM135如何调节脂质代谢， 通过其在过氧化物酶体和 DHA 合成中的作用来调节线粒体功能和视网膜功能。 具体来说，我们将 1) 检验 Tmem135 突变小鼠 DHA 水平降低的假设 造成视网膜异常，2) 确定脂肪酸的贡献 Tmem135 突变视网膜病理的合成途径，以及 3) 测试过氧化物酶体的作用 该项目的成功完成将揭示 RPE 中线粒体稳态的作用。 以前未知的 Tmem135 在视网膜细胞年龄依赖性变化中的作用，并确定 这些过程中涉及的因素，可能会导致新的补充或治疗 视网膜衰老和年龄相关疾病的选择。

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.

• 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