Nuclear receptor driven mechanisms in aging and AMD

摘要 干性老年性黄斑变性(AMD)是西方世界视力丧失的主要原因， 复杂的病因。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中的萎缩仍不清楚。然而，候选人 与疾病发展有关的致病途径是由一系列 流行病学、遗传学、形态学和生化研究，包括炎症、血脂失调、 细胞凋亡和RPE屏障功能障碍等。目前还没有治疗干性AMD的药物。 然而，瞄准这些途径的潜在主要监管者是一种途径。 我们的首要目标是发现核受体调节病理的分子机制。 AMD的特点。在这项建议中，我们主要研究NURR1的生物学和功能 (NR4A1，核受体相关-1蛋白)，一种孤儿核受体，在易患AMD的细胞中。研究 以及一些全身性疾病揭示了NURR1是一种 多种生物过程，包括细胞增殖、分化、凋亡、炎症、脂质 动态平衡和新陈代谢，强调其在整体细胞健康中的重要性。然而，作为核受体， 它的作用也被证明是不同的，并且是配体和细胞/组织特有的。考虑到进程之间的重叠 受NURR1和那些在AMD的发展和进展中起重要作用的基因调控，我们建议 系统研究NURR1的S在包括RPE、AS在内的眼细胞中的作用和治疗靶向的潜力 这一点还有待发现。 在这里，我们建立在初步观察的基础上，包括：(1)人RPE细胞中NURR1表达减少 (2)NURR1在人AMD供体组织的玻璃膜和基底沉积中呈细胞外蓄积； NURR1激活减轻TNFa诱导的RPE上皮细胞向间充质细胞(EMT)的转化 口服NURR1激活配体改善小鼠模型的视觉功能缺陷 几种干性AMD表型。我们的发现共同支持了NURR1中与年龄相关的妥协- RPE细胞动态平衡的机制。基于我们的初步数据，我们提出了三个具体的测试目标 NURR1代表AMD治疗靶点同时调节异常的假说 在易患AMD的细胞中，RPE屏障功能、细胞脂代谢和炎症。

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, including inflammation, lipid dysregulation, apoptosis, and RPE barrier dysfunction among others. Currently there are no drugs available to treat dry AMD. However, targeting a potential master regulator of these pathways is one avenue to pursue. Our overarching goal is to discover molecular mechanisms by which nuclear receptors modulate pathologies characteristic of AMD. In this proposal we concentrate on investigating the biology and function of NURR1 (NR4A1, Nuclear Receptor Related-1 protein), an orphan nuclear receptor, in cells vulnerable in AMD. Studies of the central nervous system as well as some systemic diseases have revealed NURR1 as a regulator of a variety of biological processes including cellular proliferation, differentiation, apoptosis, inflammation, lipid homeostasis and metabolism, highlighting its importance in overall cell health. However, as a nuclear receptor, its role has also been shown to vary and be ligand and cell/tissue specific. Given the overlap between process regulated by NURR1 and those important in the development and progression of AMD, we propose to systematically investigate NURR1’s role and potential for therapeutic targeting in ocular cells including RPE, as this has yet to be discovered. Herein we build on preliminary observations including (1) NURR1 expression in human RPE cells decreases with age; (2) NURR1 accumulates extracellularly in drusen and basal deposits of human AMD donor tissue; (3) NURR1 activation attenuates TNFa-induced RPE epithelial-to-mesenchymal (EMT) transition in vitro; and (4) oral administration of a NURR1 activating ligand ameliorates visual function deficits in a mouse model featuring several dry AMD phenotypes. Our findings collectively support an age-related compromise in NURR1- mechanisms in RPE cellular homeostasis. Based on our preliminary data we propose three specific aims to test the hypothesis that NURR1 represents a therapeutic target for AMD by simultaneously regulating aberrant RPE barrier function, cellular lipid metabolism, and inflammation, in cells vulnerable in AMD.