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

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.

视网膜色素上皮细胞（RPE）促进光感受器的存活。的RPE 含有丰富的线粒体，与具有各种能量密集的代谢活性组织一致 任务我们对出生后RPE选择性切除Tfam的小鼠的视网膜表型进行了表征， (RPEΔTfam）证实了RPE线粒体功能对于该上皮完整性的必要性，并且 对于感光细胞的健康。RPE-选择性敲除Tfam导致RPE-细胞自主和非- 细胞自主效应，包括感光细胞功能和数量的逐渐丧失。我们的研究结果 补充研究表明RPE是遗传性视网膜病变患者眼部病理的部位 线粒体缺陷，并支持RPE线粒体功能障碍在年龄相关性黄斑病变中的因果作用。 退行性变（AMD）。我们的初步研究已经发现了一个信号通路，在正常情况下是静止的。 RPE细胞和不同应激源诱导; RPEΔTfam小鼠RPE中FGF 21显著上调， 分散到神经视网膜暗示这种分泌的分子作为一个关键的信号，能够传播 视网膜色素上皮细胞线粒体损伤的负面影响。我们建议检验这一假设并了解 FGF 21影响应激小鼠视网膜的机制。在目标1中，我们将使用小鼠模型来 确定在RPE背景下FGF 21功能的丧失和获得对视网膜表型的后果 线粒体功能障碍在目标2中，我们将确定FGF 21自分泌和旁分泌对细胞增殖的贡献。 视网膜表型，包括细胞转录反应。在目标3中，我们将开发 FGF 21的分子抑制剂，并测试它们在RPE窘迫小鼠模型中的功效。鉴于的中心地位 视网膜色素上皮线粒体功能与视网膜稳态及慢性应激反应的相关性 疾病，包括AMD，这种RPE衍生的线粒体的后果的机械理解， 从基本和应用的角度来看，遇险信号都可能产生重大的长期影响。