Nuclear receptor driven mechanisms in aging and AMD

衰老和 AMD 中的核受体驱动机制

• 批准号: 10672924
• 负责人: Goldis Malek
• 金额: $ 47.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672924
• 关键词: Affect; Age; Age related macular degeneration; Aging; Agonist; Apoptosis; Atrophic; Attenuated; Biochemical; Biological Process; Biology; Blindness; Blood-Retinal Barrier; Bruch' s basal membrane structure; Cell Proliferation; Cell physiology; Cells; Central Nervous System; Characteristics; Complex; Data; Deposition; Development; Disease; Drug Metabolic Detoxication; Drusen; Elderly; Epidemiology; Epithelial Cells; Epithelium; Etiology; Exposure to; Eye; FOXM1 gene; Functional disorder; Genetic; Goals; Grant; Health; Homeostasis; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Knowledge; Ligands; Link; Lipids; Macrophage; Mesenchymal; Metabolism; Microglia; Molecular; Monitor; Morphology; NR4A1 gene; NR4A2 gene; Nonexudative age-related macular degeneration; Nuclear Orphan Receptor; Nuclear Receptors; Oral Administration; Oxidants; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Play; Process; Proteins; Reactive Oxygen Species; Retina; Role; Severities; Signal Pathway; Structure of retinal pigment epithelium; System; Systemic disease; Testing; Therapeutic; Therapeutic Use Study; Tissue Donors; Tissues; Toxic effect; Vision; Western World; Wild Type Mouse; age related; aged; cytokine; design; efficacy evaluation; epithelial injury; epithelial to mesenchymal transition; extracellular; forkhead protein; gain of function; human old age (65+); in vitro Model; in vivo; in vivo Model; lipid metabolism; loss of function; mouse model; neuroprotection; novel; photoreceptor degeneration; prevent; protein activation; protein expression; response; stressor; therapeutic evaluation; therapeutic target; transcription factor; transdifferentiation

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.

概括 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， 视网膜色素上皮（RPE）细胞发生的基本异常，导致 然而，AMD 中它们的进行性功能障碍和随后的萎缩仍然未知。 与疾病发展相关的致病途径是由多种因素的汇聚而产生的 流行病学、遗传学、形态学和生化研究，包括炎症、脂质失调、 细胞凋亡、RPE 屏障功能障碍等，目前尚无药物可用于治疗干性 AMD。 然而，针对这些途径的潜在主调节器是一种追求的途径。 我们的首要目标是发现核受体调节病理的分子机制 在本提案中，我们集中研究 NURR1 的生物学和功能。 （NR4A1，核受体相关 1 蛋白），一种孤儿核受体，存在于 AMD 研究中易受影响的细胞中。 中枢神经系统以及一些全身性疾病的研究表明 NURR1 是一个调节因子 多种生物过程，包括细胞增殖、分化、凋亡、炎症、脂质 体内平衡和新陈代谢，突显其在整体细胞健康中的重要性。 鉴于过程之间的重叠，其作用也被证明是不同的，并且是配体和细胞/组织特异性的。 受 NURR1 调节以及在 AMD 的发展和进展中重要的那些，我们建议 清楚地研究了 NURR1 在包括 RPE 在内的眼细胞中的作用和治疗靶向潜力，如 这还有待发现。 在此，我们基于初步观察结果，包括 (1) 人类 RPE 细胞中的 NURR1 表达降低 随着年龄的增长；(2) NURR1 在人类 AMD 供体组织的玻璃疣和基底沉积物中积累； NURR1 激活可减弱 TNFa 诱导的 RPE 上皮间质 (EMT) 体外转变；(4) 口服 NURR1 激活配体可改善小鼠模型的视觉功能缺陷 我们的研究结果共同支持 NURR1- 中与年龄相关的妥协。 根据我们的初步数据，我们提出了三个具体的测试目标。 假设 NURR1 通过同时调节异常基因来代表 AMD 的治疗靶点 AMD 中易受影响的细胞中的 RPE 屏障功能、细胞脂质代谢和炎症。