FGF21 as a mediator of RPE mitochondrial dysfunction

FGF21 作为 RPE 线粒体功能障碍的介质

• 批准号: 10586472
• 负责人: Douglas E. Vollrath
• 金额: $ 53.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586472
• 关键词: Ablation; Adverse effects; Affect; Age; Age related macular degeneration; Atrophic; Cell Culture Techniques; Cessation of life; Chronic stress; Complement; Coupling; Culture Media; Data; Defect; Distress; Electron Transport; Epithelium; Eye; FGF21 gene; Foundations; Genes; Genetic Transcription; Homeostasis; Hypertrophy; Individual; Inherited; Knock-out; Light; Link; Lipids; Mediator; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Nerve; Neural Retina; Ocular Pathology; Output; Oxidative Phosphorylation; Pathology; Peptides; Personal Satisfaction; Phenotype; Photoreceptors; Power Plants; Protein Secretion; Residual state; Retina; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Sirolimus; Site; Stress; Structure; Structure of retinal pigment epithelium; Testing; Time; Tissues; Up-Regulation; Vision; autocrine; biological adaptation to stress; cell motility; cell type; fibroblast growth factor 21; human disease; improved; inhibitor; insight; mTOR Inhibitor; mimetics; mitochondrial dysfunction; mouse model; paracrine; postnatal; receptor; response; stressor; success; therapy development; transcriptome; transcriptomics; Ablation; Adverse effects; Affect; Age; Age related macular degeneration; Atrophic; Cell Culture Techniques; Cessation of life; Chronic stress; Complement; Coupling; Culture Media; Data; Defect; Distress; Electron Transport; Epithelium; Eye; FGF21 gene; Foundations; Genes; Genetic Transcription; Homeostasis; Hypertrophy; Individual; Inherited; Knock-out; Light; Link; Lipids; Mediator; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Nerve; Neural Retina; Ocular Pathology; Output; Oxidative Phosphorylation; Pathology; Peptides; Personal Satisfaction; Phenotype; Photoreceptors; Power Plants; Protein Secretion; Residual state; Retina; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Sirolimus; Site; Stress; Structure; Structure of retinal pigment epithelium; Testing; Time; Tissues; Up-Regulation; Vision; autocrine; biological adaptation to stress; cell motility; cell type; fibroblast growth factor 21; human disease; improved; inhibitor; insight; mTOR Inhibitor; mimetics; mitochondrial dysfunction; mouse model; paracrine; postnatal; receptor; response; stressor; success; therapy development; transcriptome; transcriptomics

The retinal pigment epithelium (RPE) nourishes and promotes survival of photoreceptors. The RPE contains abundant mitochondria, consistent with a metabolically active tissue with a variety of energy intensive tasks. Our characterization of the retinal phenotype of mice with postnatal RPE-selective ablation of Tfam (RPEΔTfam) demonstrates the necessity of RPE mitochondrial function for the integrity of this epithelium, and for the well being of photoreceptors. RPE-selective knockout of Tfam results in RPE-cell autonomous and non- cell autonomous effects including a progressive loss of photoreceptor function and numbers. Our findings complement studies implicating the RPE as the site of ocular pathology in individuals with inherited mitochondrial defects, and support a causal role for for RPE mitochondrial dysfunction in age-related macular degeneration (AMD). Our preliminary studies have uncovered a signaling pathway that is quiescent in normal RPE cells and induced by diverse stressors; striking upregulation of FGF21 in the RPE of RPEΔTfam mice and dispersion to the neural retina implicates this secreted molecule as a critical signal capable of propagating the negative effects of RPE mitochondrial distress. We propose to test this hypothesis and understand the mechanisms by which FGF21 affects the stressed mouse retina. In Aim 1, we will use mouse models to determine the consequences of loss and gain of FGF21 function on retinal phenotype in the context of RPE mitochondrial dysfunction. In Aim 2, we will determine the FGF21 autocrine and paracrine contributions to the retinal phenotype in this context, including cellular transcriptional responses. In Aim 3, we will develop molecular inhibitors of FGF21 and test their efficacy in mouse models of RPE distress. Given the centrality of RPE mitochondrial function to retinal homeostasis and the relevance of chronic stress responses to human diseases, including AMD, a mechanistic understanding of the consequences of this RPE-derived mitochondrial distress signal could have a substantial long term impact from both basic and applied perspectives.

视网膜色素上皮（RPE）滋养并促进感光体的存活。 RPE 包含丰富的线粒体，与具有多种能量密集型的代谢活性组织一致 任务。我们用产后RPE选择TFAM的小鼠视网膜表型的表征 （RPEΔTFAM）证明了该上皮完整性的必要RPE线粒体功能，并且 对于光感受器的井。 TFAM的RPE选择性敲除导致RPE细胞自主和非 - 细胞自主效应，包括逐渐丧失光感受器功能和数量。我们的发现 补充研究将RPE视为遗传的个体中的眼病理部位 线粒体缺陷并支持与年龄相关的黄斑中RPE线粒体功能障碍的因果作用 变性（AMD）。我们的初步研究发现了一种在正常情况下静止的信号通路 RPE细胞并由潜水应激源诱导；在RPEΔTFAM小鼠的RPE中触及FGF21的上调，并 对神经视网膜的分散将这种分泌的分子作为能够传播的关键信号 RPE线粒体困扰的负面影响。我们建议检验这一假设并了解 FGF21影响应力小鼠视网膜的机制。在AIM 1中，我们将使用鼠标模型来 确定在RPE的背景下，FGF21功能损失和增益对残留表型的后果 线粒体功能障碍。在AIM 2中，我们将确定FGF21自分泌和旁分泌的贡献 在这种情况下，视网膜表型，包括细胞转录反应。在AIM 3中，我们将发展 FGF21的分子抑制剂并测试其在RPE遇险模型中的效率。考虑到中心 RPE线粒体功能与视网膜稳态以及慢性应激反应的相关性 包括AMD在内的疾病，对这种RPE衍生的线粒体的后果的机械理解 遇险信号从基本和应用的角度都可能产生重大的长期影响。