Regulation of inflammation and lipid homeostasis by the aryl hydrocarbon receptor in age-related macular degeneration

年龄相关性黄斑变性中芳烃受体对炎症和脂质稳态的调节

• 批准号: 9542513
• 负责人: Goldis Malek
• 金额: $ 44.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542513
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Affect; Age; Age related macular degeneration; Agonist; Anti-inflammatory; Aryl Hydrocarbon Receptor; Atrophic; Autophagocytosis; Biochemical; Blindness; Bruch' s basal membrane structure; CD36 gene; Cells; Cholesterol; Cholesterol Homeostasis; Complex; Data; Deposition; Development; Diabetic Retinopathy; Disease; Drusen; Epidemiology; Epithelial; Etiology; Eye; Functional disorder; Genetic; Grant; Health; Homeostasis; Human; Hydrolysis; Immune; Impairment; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Ligands; Link; Lipids; Microglia; Monitor; Morphology; Mus; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Permeability; Pharmaceutical Preparations; Phenotype; Prevention; Production; Proliferative Vitreoretinopathy; Receptor Activation; Regulation; Reporting; Retinal; Retinal Diseases; Retinal Pigments; Role; Signal Pathway; Signal Transduction Pathway; Structure of retinal pigment epithelium; Testing; Thick; Tissues; Toxic Environmental Substances; Toxic effect; Toxin; Vision; Western World; Wild Type Mouse; Xenobiotic Metabolism; age related; aged; aryl hydrocarbon receptor ligand; base; cell type; cytokine; design; experimental study; human old age (65+); improved; in vitro Model; in vivo; interest; macrophage; mouse model; novel; protein degradation; proteostasis; response; therapeutic evaluation; therapeutic target; transcription factor

Project Summary: Dry age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World with a complex etiology. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) cells, resulting in their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate pathogenic pathways linked to development of disease have emerged from the convergence of a sundry of epidemiological, genetic, morphological, and biochemical studies. Of these mechanistic pathways, three are strongly associated with initiation and progression of AMD and include inflammation, lipid dysregulation, and impaired protein degradation and clearance. Currently there are no drugs available to treat dry AMD. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor activated by a diverse array of endogenous and environmental compounds including toxins and lipids. It has been studied extensively in the context of its role as a regulator of the cellular response to environmental toxicants. However, recent reports highlight non-classical mechanisms of AhR, most notably regulation of inflammatory pathways, cholesterol homeostasis, and autophagy/lysosomal function and permeability, pathways also important in the pathogenesis of AMD. Importantly, mechanisms regulated by AhR have been shown to be ligand and cell/tissue specific (e.g. toxic or pro-inflammatory response in one cell type yet anti-inflammatory in another cell type). As such, we are interested in investigating mechanisms underlying the AhR-mediated signal transduction pathway in RPE cells and the consequence of AhR activation on RPE health to counter injury and dysfunction. Our preliminary studies show that the activity of the AhR decreases as a function of age in human RPE cells. Additionally we have observed that aged AhR knockout (AhR-/-) mice develop phenotypic features of dry AMD, including thick continuous sub- RPE deposits, RPE dysfunction and degeneration, and accumulation of sub-retinal immune cells. Our findings not only support the potential importance of this signaling pathway in the pathogenesis of AMD, but also suggest an age-related compromise in AhR-mechanisms associated with normal RPE cellular clearance. Three specific aims have been proposed to test our hypothesis that the AhR represents a therapeutic target for prevention and treatment of AMD by simultaneously regulating aberrant cholesterol homeostasis and pro-inflammatory pathways in cells vulnerable in AMD.

项目摘要： 与年龄相关的黄斑变性（AMD）是西方世界视力丧失的主要原因 复杂的病因。视网膜色素上皮（RPE）细胞中发生的基本异常，导致 他们的进行性功能障碍和随后在AMD中的萎缩尚不清楚。但是，候选病原体 与疾病发展相关的途径是由于流行病学杂物的融合而出现的 遗传，形态学和生化研究。在这些机械途径中，三个密切相关 随着AMD的启动和进展，包括炎症，脂质失调和蛋白质受损 退化和清除。目前尚无可用药物来治疗干燥AMD。 芳基烃受体（AHR）是由配体依赖的转录因子，该转录因子被多种阵列激活 内源性和环境化合物，包括毒素和脂质。它已经在 其作为对环境有毒物质细胞反应的调节剂的作用的背景。但是，最近的报告 突出显示AHR的非古典机制，最著名的是炎症途径的调节，胆固醇 稳态，自噬/溶酶体功能和渗透率，途径在发病机理中也很重要 AMD。重要的是，由AHR调节的机制已显示为配体和细胞/组织特异性（例如， 一种细胞类型中的有毒或促炎反应，但在另一种细胞类型中抗炎）。因此，我们是 有兴趣研究RPE细胞中AHR介导的信号转导途径的基础机制 AHR激活对RPE健康的后果应对损伤和功能障碍。我们的初步研究 表明AHR的活性随着人RPE细胞年龄的函数而降低。另外我们已经观察到 老化的AHR敲除（AHR - / - ）小鼠会发展出干燥AMD的表型特征，包括厚连续的子 - RPE沉积，RPE功能障碍和变性以及视网膜免疫细胞的积累。我们的发现不是 仅支持该信号通路在AMD发病机理中的潜在重要性，但也表明 与正常RPE细胞清除相关的AHR机制中与年龄相关的妥协。三个具体目标 已经提出要检验我们的假设，即AHR代表了预防和 通过同时调节异常胆固醇稳态和促炎途径来治疗AMD 在AMD中脆弱的细胞中。