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

基本信息

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
项目类别：
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

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

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项目摘要

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：Claudio Punzo 项目摘要在人类中导致地理萎缩（GA）的视网膜色素上皮萎缩（RPE）是其中之一工业化世界中失明的主要原因。这是因为目前没有治疗可用于防止RPE萎缩，从而可以GA，这是一种与年龄相关的黄斑的高级形式变性（AMD）。该疾病的特征是局灶性RPE细胞损失。因为RPE保持感光体稳态，光感受器也死亡，然后导致失明。最近，已经认识到光感受器的高代谢需求可能导致AMD的疾病进展，特别是因为光感受器和RPE代谢紧密相连。两个关键发现暗示疾病发病机理中的感光体。首先，软drusen和视视螺母沉积物的分布分别反映锥和杆的分布。这导致了代谢需要的提议光感受器是驱动沉积形成的原因。第二，黄斑易位程序，是开发以从垂死的RPE细胞中节省黄斑锥的开发表明，锥的新区域易位的重新开发的GA。在这里，人们认为锥体的高代谢需求是原因 RPE应力。但是，光感受器代谢是否在AMD患者和未诊断的患者之间有所不同个人仍然不清楚。我们最近表明，AMD患者的PR表现出营养的迹象推导与对葡萄糖短缺的适应性反应相关的基因上调。经过模仿小鼠光感受器中的这种适应性反应，我们能够诱导一部分病理学让人想起那些在AMD的人类中看到的，包括局灶性RPE萎缩。这个项目的目标是确定到底是什么导致了所见病理。我们建议在AIM 1中进一步分析我们的模型和确定RPE细胞如何死亡。此后，在AIM 2中，我们将在遗传上剖析我们的信号传导途径为了磨练引起的代谢变化，用于操纵感光者代谢疾病。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识别基础基因表达变化，导致疾病并在体内检测假定的候选机制。拟议研究的完成将有助于了解感光体如何导致RPE萎缩。