Elucidating the mechanism of erythropoietin (EPO) in mitigating Dry-AMD pathophysiology

阐明促红细胞生成素 (EPO) 缓解干性 AMD 病理生理学的机制

基本信息

批准号：
10521937
负责人：
Manas R Biswal
金额：
$ 41.15万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521937
关键词：
3-nitrotyrosine 5&apos -AMP-activated protein kinase Adipocytes Age Age related macular degeneration Age-Months Aging Animal Model Animals Anti-Inflammatory Agents Antioxidants Atrophic Bioenergetics Biogenesis Biological Biological Markers Blindness Cell Death Cells Cessation of life Cholesterol Choroid Complement Cytoprotection Dark Adaptation Deposition Developed Countries Diet Disease Economic Burden Effectiveness Electron Microscopy Enzyme-Linked Immunosorbent Assay Erythropoietin Eye Fatty acid glycerol esters Flow Cytometry Functional disorder Gene Activation Gene Proteins Genes Genetic Polymorphism Genetic Transcription Genotype Global Change Glutathione Harvest Health Histologic Homeostasis Immunohistochemistry Impairment Individual Inflammation Interleukin-1 alpha Interleukin-10 Interleukin-17 Interleukin-18 Interleukin-6 Ions Iron Lipid Peroxidation Lipids Measures Mediating Mitochondria Modeling Molecular Monitor Mus Mutation Nonexudative age-related macular degeneration Oxidative Stress Oxidative Stress Induction Pathology Pathway Analysis Pathway interactions Patients Phenotype Photoreceptors Play Protein Isoforms Protein Kinase Proteins Proteomics Quality of life RNA Recombinant adeno-associated virus (rAAV)Reporting Research Retina Retinal Degeneration Retinal Pigments Risk Role Serotyping Signal Transduction Stains Stress Structure Structure of retinal pigment epithelium Symptoms TNF gene Techniques Testing Therapeutic Intervention Time Tissue Harvesting Transgenic Mice Tumor-infiltrating immune cells Variant Vision Visual Acuity Western Blotting age related aged cell type clinical phenotype cytokine delivery vehicle digital effective therapy fundus imaging ganglion cell geographic atrophy health care economics improved functioning in vivo evaluation interest macula mouse model novel novel therapeutics oxidative DNA damage preservation prevent preventive intervention productivity loss protective effect response retinal imaging single cell sequencing subretinal injection transcriptome sequencing vector visual dysfunction

项目摘要

PROJECT SUMMARY Age-related macular degeneration (AMD) is one of the leading causes of irreversible visual dysfunction in older individuals in developed countries, resulting in loss of productivity, independence, and quality of life, as well as tremendous healthcare and economic burden. Visual dysfunction in AMD patients could be in the form of ‘‘dry’’ AMD or ‘‘wet’’ AMD or both. While some treatments are available for wet-AMD, but there is no effective treatment for geographic atrophy (GA), the advanced form of dry-AMD. Oxidative stress-induced cellular changes play a significant role in the loss of macular RPE and photoreceptors in dry-AMD. Treatments involving local and sustained delivery of molecules or genes to counteract oxidative stress-induced cellular changes could prevent RPE atrophy. Systemic or retinal delivery EPO-R76E, a modified form of EPO (with reduced erythropoietic activity) improved the function of ganglion cells and photoreceptors cells in the retina. Because of its effect in preventing cell death due to induction oxidative stress, we are especially interested in investigating the precise mechanism(s) of how RPE specific EPO-R76E interacts with other retinal cells and influences aberrant molecular pathways in controlling dry-AMD phenotype. We will interrogate the impact of EPO-R76E using two different animal models showing AMD pathology; one is associated with induction of RPE oxidative stress, and the other due to complement dysregulation. We will use recombinant adeno-associated virus (AAV) with serotype 1 to achieve sustained expression of EPO-R76E and deliver to mice eye via subretinal injection. Our first aim will test molecular mechanisms of the retinal protection by EPO-R76E using proteomics analyses of pathways and cell- specific transcriptional approaches in a mouse model of dry-AMD. Our second aim will test whether sustained expression of EPO-R76E ameliorates dry AMD phenotypes in animal models and interrogate how late in the course of retinal degeneration EPO-R76E will be effective in preventing disease symptoms. Our research will elucidate the role of EPO signaling in RPE function, retinal health, and the approach for preventive or therapeutic intervention of dry-AMD. These studies will identify novel molecular pathways for manipulating the retina and provide a new direction for managing dry-AMD.

项目摘要与年龄相关的黄斑变性（AMD）是较老的视觉功能障碍的主要原因之一发达国家的个人，导致生产力，独立性和生活质量的丧失以及巨大的医疗保健和经济伯恩。 AMD患者的视觉功能障碍可能是``干燥''的形式 AMD或``湿''AMD或两者兼而有之。虽然有些治疗可用于湿AMD，但没有有效的治疗方法对于地理萎缩（GA），干燥的晚期形式。氧化应激诱导的细胞变化的作用在干燥AMD中黄斑RPE和光感受器的丢失中的重要作用。涉及当地的治疗分子或基因持续递送以抵消氧化应激诱导的细胞变化 RPE萎缩。全身或视网膜递送EPO-R76E，一种修饰的EPO形式（促红细胞生成活性）改善了视网膜中神经节细胞和感光细胞的功能。因为它的影响防止诱导氧化应激引起的细胞死亡，我们特别有兴趣研究精确的 RPE特异性EPO-R76E如何与其他永久细胞相互作用并影响异常分子的机制控制干燥AMD表型的途径。我们将使用两种不同的表现出AMD病理学的动物模型；一个与诱导RPE氧化应激有关，另一个与由于补体失调。我们将使用具有血清型1至的重组腺相关病毒（AAV）实现EPO-R76E的持续表达，并通过视网膜下注射传递到小鼠眼睛。我们的第一个目标将测试 EPO-R76E的视网膜保护的分子机制，使用途径和细胞的保护分析在干amd的小鼠模型中采用特定的转录方法。我们的第二个目标将测试是否持续 EPO-R76E的表达可改善动物模型中的干燥AMD表型，并询问在视网膜变性epo-R76E的过程将有效预防疾病症状。我们的研究会阐明EPO信号在RPE功能，残留健康以及预防或治疗方法中的作用干燥AMD的干预。这些研究将确定操纵视网膜的新分子途径提供了管理干燥AMD的新方向。