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.

项目概要年龄相关性黄斑变性（AMD）是老年人不可逆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损失，以及 AMD 患者的巨大医疗保健和经济负担可能表现为“干性”视力障碍。 AMD 或“湿性”AMD 或两者兼而有之。虽然有一些治疗方法可用于治疗湿性 AMD，但没有有效的治疗方法。对于地理萎缩 (GA)，干性 AMD 的高级形式发挥着重要作用。在干性 AMD 治疗中，黄斑 RPE 和光感受器的丧失具有重要作用。持续传递分子或基因来抵消氧化应激引起的细胞变化可以预防 RPE 萎缩。全身或视网膜输送 EPO-R76E，EPO 的改良形式（红细胞生成减少）活性）改善了视网膜神经节细胞和感光细胞的功能。防止诱导氧化应激引起的细胞死亡，我们特别感兴趣的是研究精确的 RPE 特异性 EPO-R76E 如何与其他视网膜细胞相互作用并影响异常分子的机制我们将使用两种不同的方法来探究 EPO-R76E 的影响。显示 AMD 病理学的动物模型；一种与 RPE 氧化应激的诱导有关，另一种与 RPE 氧化应激的诱导有关。由于补体失调，我们将使用血清型 1 的重组腺相关病毒 (AAV) 来治疗。实现 EPO-R76E 的持续表达并通过视网膜下注射递送至小鼠眼部我们的首要目标是进行测试。利用途径和细胞的蛋白质组学分析，研究 EPO-R76E 视网膜保护的分子机制我们的第二个目标是测试干性 AMD 小鼠模型中的特定转录方法是否持续。 EPO-R76E 的表达可改善动物模型中的干性 AMD 表型，并探究该现象发生的时间有多晚我们的研究将在视网膜变性过程中有效预防疾病症状。阐明 EPO 信号在 RPE 功能、视网膜健康以及预防或治疗方法中的作用这些研究将确定操纵视网膜和视网膜的新分子途径。为管理干性 AMD 提供了新的方向。