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

PI：Claudio Punzo 项目摘要 导致人类地图状萎缩（GA）的视网膜色素上皮萎缩（RPE）是视网膜色素变性的一种。 是工业化国家失明的主要原因。这是因为目前没有治疗方法 可用于预防RPE萎缩，从而防止GA，这是一种与视网膜病变相关的黄斑变性的高级形式。 变性（AMD）。该疾病的特征在于局灶性RPE细胞损失。因为RPE维持着 光感受器稳态，光感受器也死亡，然后导致失明。近日有 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代谢紧密相连。两个关键发现表明 光感受器在疾病发病机制中的作用一、软性玻璃疣和视网膜下玻璃疣样沉积物的分布 分别反映了锥体和杆状体的分布。这导致了一种观点，即代谢需要 是驱动存款形成的原因。第二，黄斑移位手术， 为了从垂死的RPE细胞中拯救黄斑视锥细胞而开发的新技术揭示了视锥细胞的新区域， 易位再发育GA。在这里，它被认为是高代谢需求的锥是什么原因 RPE应激。然而，是否光感受器代谢在AMD患者和非疾病之间存在差异， 个人仍然不清楚。我们最近发现，AMD患者的PR显示出营养不良的迹象， 因为它们上调与葡萄糖缺乏的适应性反应相关的基因。通过 在小鼠光感受器中模拟这种适应性反应，我们能够诱导一种病理学亚组， 这让人联想到在患有AMD的人类中看到的那些，包括局灶性RPE萎缩。该项目的目标是 确定到底是什么导致了所见的病理。我们在目标1中建议进一步分析我们的模型， 决定RPE细胞如何死亡此后，在目标2中，我们将从遗传学的角度剖析我们 已经习惯于操纵感光细胞的新陈代谢，以磨练在新陈代谢的变化， 疾病最后，在aim 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 基因表达的变化，导致疾病和测试推定的候选机制在体内。 这项研究的完成将有助于了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.