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

确定光感受器介导的视网膜色素上皮萎缩的原因

• 批准号: 10403650
• 负责人: Claudio Punzo
• 金额: $ 40.62万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403650
• 关键词: Affect; Age; Age related macular degeneration; Animal Model; Area; Atrophic; Autophagocytosis; Blindness; Candidate Disease Gene; Cell Death; Cells; Cellular Metabolic Process; Cessation of life; Characteristics; Complement; Complex; Cone; Data; Deposition; Derivation procedure; Disease; Disease Progression; Docosahexaenoic acid supplementation; Drusen; Ecosystem; Electroporation; Event; FRAP1 gene; Fatty Acids; Functional disorder; Gene Expression; Genes; Genetic Transcription; Glucose; Glycolysis; Goals; Health; Hexokinase 2; Homeostasis; Human; Impairment; Individual; Industrialization; Lead; Link; Lipoproteins; Location; Long-Term Effects; Lysosomes; Mediating; Metabolic; Metabolism; Modeling; Mus; Nutrient; Pathogenesis; Pathology; Pathway interactions; Patients; Phase; Phosphotransferases; Photoreceptors; Procedures; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Research; Retina; Retinitis Pigmentosa; Rod; Signal Pathway; Signal Transduction; Stress; Structure of retinal pigment epithelium; Testing; Time; Translations; Tuberous Sclerosis; Vertebrate Photoreceptors; advanced disease; density; dietary; geographic atrophy; in vivo; lipidomics; macula; metabolomics; photoreceptor degeneration; plasmid DNA; postnatal; prevent; response; transcriptome sequencing; transcriptomics

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.

PI：克劳迪奥·庞佐 项目概要 导致人类地理萎缩（GA）的视网膜色素上皮萎缩（RPE）是其中之一 工业化国家失明的主要原因。这是因为目前没有治疗方法 可预防 RPE 萎缩，从而预防 GA，这是年龄相关性黄斑的一种高级形式 变性（AMD）。该疾病的特征是局灶性 RPE 细胞丢失。因为 RPE 维持 如果光感受器稳态失衡，光感受器也会死亡，从而导致失明。最近，已经 认识到光感受器的高代谢需求可能会导致 AMD 疾病进展， 特别是，因为光感受器和 RPE 代谢紧密相连。两个重要发现表明 光感受器在疾病发病机制中的作用。一、软玻璃膜疣和视网膜下玻璃膜疣沉积物的分布 分别反映视锥细胞和视杆细胞的分布。这导致了代谢需求的提议 光感受器的数量是驱动沉积物形成的因素。其次，黄斑移位手术， 开发用于从垂死的 RPE 细胞中拯救黄斑锥体的研究表明，视锥细胞所在的新区域 易位重新开发的GA。据认为，视锥细胞的高代谢需求是导致 RPE 压力。然而，AMD 患者和未患病患者的光感受器代谢是否存在差异？ 个人仍不清楚。我们最近发现 AMD 患者的 PR 显示出营养迹象 推导是因为它们上调与葡萄糖短缺适应性反应相关的基因。经过 模仿小鼠光感受器的这种适应性反应，我们能够诱导出一组病理学， 让人想起患有 AMD 的人类，包括局灶性 RPE 萎缩。该项目的目标是 确定造成所见病理现象的确切原因。我们在目标 1 中建议进一步分析我们的模型并 确定 RPE 细胞如何死亡。此后，在目标 2 中，我们将从基因角度剖析我们所研究的信号通路。 已用于操纵光感受器代谢，以磨练引起的代谢变化 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识别潜在的 导致疾病的基因表达变化并在体内测试假定的候选机制。 拟议研究的完成将有助于了解光感受器如何导致 RPE 萎缩。