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

项目摘要： 干性年龄相关性黄斑变性（AMD）是西方世界视力丧失的主要原因， 复杂的病因学视网膜色素上皮（RPE）细胞中发生的基本异常，导致 它们在AMD中的进行性功能障碍和随后的萎缩仍然未知。然而，候选致病性 与疾病发展有关的途径是由一系列流行病学， 遗传学、形态学和生物化学研究。在这些机制途径中，有三个与 与AMD的发生和进展有关，包括炎症、脂质失调和蛋白质受损， 降解和清除。目前没有药物可用于治疗干性AMD。 芳烃受体（AhR）是一种由多种阵列激活的配体依赖性转录因子 内源性和环境化合物，包括毒素和脂质。它已被广泛研究， 它作为细胞对环境毒物反应的调节剂的作用。然而，最近的报告 强调AhR非经典机制，最显著的是炎症途径、胆固醇 自噬/溶酶体功能和渗透性，这些途径在发病机制中也很重要 关于AMD重要的是，AhR调节的机制已被证明是配体和细胞/组织特异性的（例如， 在一种细胞类型中毒性或促炎反应，而在另一种细胞类型中抗炎）。因此，我们 对研究RPE细胞中AhR介导的信号转导途径的机制感兴趣 以及AhR激活对RPE健康的后果，以对抗损伤和功能障碍。我们的初步研究 显示AhR的活性在人RPE细胞中作为年龄的函数而降低。此外，我们还观察到 老年AhR敲除（AhR-/-）小鼠发展出干性AMD的表型特征，包括厚的连续亚细胞， RPE沉积、RPE功能障碍和变性以及视网膜下免疫细胞的积聚。我们的发现并不 这不仅支持了该信号通路在AMD发病机制中的潜在重要性，而且还提示了 与正常RPE细胞清除相关的AhR机制的年龄相关性损害。三个具体目标 已经提出来测试我们的假设，即AhR代表了预防的治疗靶点， 通过同时调节异常胆固醇稳态和促炎途径治疗AMD 在易受AMD影响的细胞中。

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.