Nuclear receptor driven mechanisms in aging and AMD

衰老和 AMD 中的核受体驱动机制

• 批准号: 10448330
• 负责人: Goldis Malek
• 金额: $ 45.85万
• 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/10448330
• 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; Characteristics; Complex; Data; Deposition; Development; Disease; Drug Metabolic Detoxication; Drusen; Elderly; Epidemiology; Epithelial; Epithelial Cells; Etiology; Exposure to; Eye; FOXM1 gene; Functional disorder; Genetic; Goals; Grant; Health; Homeostasis; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Knowledge; Ligands; Link; Lipids; Mesenchymal; Metabolism; Microglia; Molecular; Monitor; Morphology; NR4A1 gene; NR4A2 gene; Neuraxis; Nonexudative age-related macular degeneration; Nuclear Receptors; Oral Administration; Orphan; Oxidants; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Play; Process; Proteins; Reactive Oxygen Species; Retina; Retinal Pigments; 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; base; cytokine; design; efficacy evaluation; epithelial injury; epithelial to mesenchymal transition; extracellular; forkhead protein; human old age (65+); in vitro Model; in vivo; in vivo Model; lipid metabolism; loss of function; macrophage; mouse model; neuroprotection; novel; photoreceptor degeneration; prevent; 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.

总结 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，候选人 与疾病发展相关的致病途径是由一系列 流行病学、遗传学、形态学和生物化学研究，包括炎症、脂质失调， 细胞凋亡和RPE屏障功能障碍等。目前没有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的特征。在本研究中，我们将重点研究BMPR 1的生物学和功能 （NR 4A 1，核受体相关蛋白-1），一种孤儿核受体，在AMD易感细胞中。研究 中枢神经系统以及一些系统性疾病的研究表明，ARM 1是一种调节因子， 多种生物过程包括细胞增殖、分化、凋亡、炎症、脂质过氧化反应、细胞凋亡、细胞增殖、细胞凋亡、细胞 体内平衡和代谢，突出了其在整体细胞健康中的重要性。然而，作为核受体， 它作用也显示出变化，且是配体和细胞/组织特异性的。考虑到流程之间的重叠 受AMR 1调节的蛋白质和那些在AMD的发展和进展中重要的蛋白质，我们建议 系统地研究了CRISPR 1在眼细胞（包括RPE）中的作用和治疗靶向潜力， 这还有待发现。 在此，我们建立在初步观察的基础上，包括（1）在人RPE细胞中， （2）AMD R1在人AMD供体组织的玻璃疣和基底沉积物中细胞外积累;（3） 在体外，CD 3R 1活化减弱TNF α诱导的RPE上皮向间充质（EMT）转化;和（4） 口服给予CD 3R 1活化配体改善小鼠模型的视觉功能缺陷， 几种干性AMD表型。我们的研究结果共同支持年龄相关的妥协，在CR 1- RPE细胞内稳态的机制。根据我们的初步数据，我们提出了三个具体的目标，以测试 这一假说认为，AMR 1代表了AMD的治疗靶点， AMD易感细胞中的RPE屏障功能、细胞脂质代谢和炎症。