Identifying the cause for photoreceptor-mediated retinal-pigmented epithelium atrophy

少年派：克劳迪奥·庞佐 项目摘要 视网膜色素上皮萎缩(RPE)是导致人类地理性萎缩(GA)的原因之一 在工业化世界中导致失明的主要原因。这是因为目前还没有治疗方法 可预防RPE萎缩，从而防止GA，这是年龄相关性黄斑的一种高级形式 退行性变(AMD)。该病的特点是局灶性RPE细胞丢失。因为RPE维护 光感受器的动态平衡，光感受器也会死亡，从而导致失明。最近，它一直在 认识到光感受器的高代谢需求可能有助于AMD的疾病进展， 特别是因为光感受器和RPE新陈代谢是紧密相连的。两个关键的发现意味着 光感受器在疾病发病机制中的作用第一，软性玻璃体和视网膜下玻璃体沉积的分布 分别镜像圆锥体和杆的分布。这导致了一种观点，即新陈代谢需要 光感受器的数量是形成沉积物的原因。第二，黄斑移位手术，这是 为挽救黄斑视锥细胞而开发的死亡RPE细胞揭示了视锥细胞所在的新区域 移位重新开发的GA。在这里，人们认为锥体的高代谢需求是导致 RPE应激。然而，AMD患者和非AMD患者的光感受器代谢是否存在差异 具体情况尚不清楚。我们最近发现AMD患者的PR显示出营养的迹象 因为它们上调了与对葡萄糖短缺的适应性反应相关的基因。通过 通过在小鼠光感受器中模拟这种适应性反应，我们能够诱导出一系列病理变化 与AMD患者相似，包括局灶性RPE萎缩。这个项目的目标是 找出究竟是什么导致了所看到的病理现象。我们在目标1中建议进一步分析我们的模型并 确定RPE细胞的死亡方式。此后，在目标2中，我们将从基因上剖析我们 已经习惯于操控感光器的新陈代谢，以研磨引起的新陈代谢变化 疾病。最后，在目标3中，我们将使用代谢组学、脂质组学和转录组学来确定潜在的 导致疾病的基因表达变化，并在体内测试假定的候选机制。 完成这项拟议的研究将有助于理解光感受器如何导致RPE萎缩。

PI: Claudio Punzo Project Summary Retinal-pigmented epithelium atrophy (RPE) that results in geographic atrophy (GA) in humans is one of the leading causes for blindness in the industrialized world. This is because there is currently no treatment available to prevent RPE atrophy and thus GA, which is an advanced form of Age-related Macular Degeneration (AMD). The disease is characterized by focal RPE cell loss. Because the RPE maintains photoreceptor homeostasis, photoreceptors die as well, which then leads to blindness. Recently, it has been recognized that the high metabolic demands of photoreceptors may contribute to disease progression in AMD, in particular, because photoreceptors and RPE metabolism are tightly linked. Two key findings imply photoreceptors in disease pathogenesis. First, the distribution of soft drusen and subretinal drusenoid deposits mirrors the distribution of cones and rods, respectively. This has led to the proposal that the metabolic needs of photoreceptors are what drives deposit formation. Second, macular translocation procedures, which were developed to save macular cones from dying RPE cells revealed that the new region where the cones where translocated redeveloped GA. Here it is thought that the high metabolic demands of cones are what causes RPE stress. However, whether photoreceptor metabolism differs between AMD patients and non-diseased individuals remained unclear. We recently showed that PRs of AMD patients display signs of nutrient derivation as they upregulate genes associated with an adaptive response to a glucose shortage. By mimicking this adaptive response in mouse photoreceptors we were able to induce a subset of pathologies that are reminiscent of those seen in humans with AMD, including focal RPE atrophy. The goal of this project is to identify what exactly causes the pathologies seen. We propose in aim 1 to further analyze our model and to determine how RPE cells die. Thereafter, in aim 2, we will dissect genetically the signaling pathway that we have used to manipulate photoreceptor metabolism in order to hone in on the metabolic changes that cause disease. Finally, in aim 3, we will use metabolomics, lipidomics and transcriptomics to identify the underlying gene expression changes that cause disease and test putative candidate mechanisms in vivo. Accomplishment of the proposed research will help understand how photoreceptors can cause RPE atrophy.