FGF21 as a mediator of RPE mitochondrial dysfunction

视网膜色素上皮(RPE)滋养和促进光感受器的存活。RPE 含有丰富的线粒体，与代谢活跃的组织一致，具有各种能量密集型 任务。我们对出生后选择性消融Tfam的小鼠视网膜表型的表征 (rpeΔtfam)证明了rpe线粒体功能对于该上皮的完整性的必要性，以及 为了光感受器的健康。RPE选择性敲除Tfam导致RPE细胞自主和非 细胞自主效应，包括光感受器功能和数量的进行性丧失。我们的发现 补体研究提示遗传性视网膜色素上皮是眼部病变的部位 线粒体缺陷，并支持老年性黄斑视网膜色素上皮线粒体功能障碍的原因 退行性变(AMD)。我们的初步研究发现了一条在正常情况下处于静止状态的信号通路 不同应激源诱导的视网膜色素上皮细胞FGF21在视网膜色素上皮细胞中的表达显著上调Δ小鼠和 弥散到神经视网膜意味着这种分泌的分子是一个关键信号，能够传播 RPE线粒体窘迫的负面影响。我们建议检验这一假设，并理解 FGF21影响应激小鼠视网膜的机制。在目标1中，我们将使用鼠标模型来 在RPE的背景下确定FGF21功能丧失和获得对视网膜表型的影响 线粒体功能障碍。在目标2中，我们将确定FGF21自分泌和旁分泌对 视网膜在这方面的表型，包括细胞转录反应。在目标3中，我们将开发 FGF21的分子抑制剂，并在小鼠RPE窘迫模型中测试其疗效。鉴于…的中心地位 视网膜色素上皮线粒体对视网膜稳态的作用及其与人类慢性应激反应的相关性 疾病，包括AMD，从机制上理解这种RPE衍生的线粒体的后果 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。

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.