Deciphering the role of osteopontin in the aging eye and age-related macular degeneration

破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用

• 批准号: 10679287
• 负责人: Goldis Malek
• 金额: $ 45.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679287
• 关键词: Affect; Age; Age related macular degeneration; Aging; Animal Model; Anti-Inflammatory Agents; Apoptosis; Atrophic; Autophagocytosis; Biochemical; Biology; Blindness; Blood-Retinal Barrier; Cell Differentiation process; Cell physiology; Cell secretion; Cells; Cellular Metabolic Process; Characteristics; Complex; Contrast Sensitivity; Data; Deposition; Development; Disease; Drusen; Elderly; Epidemiology; Etiology; Exposure to; Eye; Functional disorder; Genetic; Glycoproteins; Goals; Grant; Health; Homeostasis; Human; Immune; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Injury; Knowledge; Link; Lipids; Macrophage; Metabolism; Microglia; Molecular; Monitor; Morphology; Names; Neurodegenerative Disorders; Nonexudative age-related macular degeneration; Oxidants; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Pigment Epithelium; Plasma; Play; Process; Property; Protein Isoforms; Proteins; Publishing; RNA Splicing; Reporting; Retina; Role; Side; Signal Pathway; Structure of retinal pigment epithelium; System; Systemic disease; Testing; Therapeutic; Therapeutic Effect; Therapeutic Use Study; Tissue Donors; Tissues; Variant; Western World; cytokine; design; efficacy testing; extracellular; gain of function; human old age (65+); in vitro Model; in vivo; in vivo Model; loss of function; mouse model; osteopontin; phenotypic biomarker; photoreceptor degeneration; prevent; recruit; source localization; stressor; therapeutic evaluation; 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) resulting in their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate pathogenic pathways linked to the 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. In this proposal we concentrate on investigating the biology and function of osteopontin (OPN), a matricellular glycoprotein known for its involvement in the pathogenesis of a variety of neurodegenerative and systemic diseases, in which inflammation is key, in part through its role as a macrophage recruitment and retention factor. However, OPN reportedly plays a two-sided role having both pro- and anti-inflammatory properties. Furthermore, OPN has also been shown to regulate cellular homeostasis effecting cell differentiation, metabolism, autophagy, phagocytosis, and apoptosis to name a few. This potential paradox in the role of OPN may in part be due to the fact that (1) OPN function is cell and tissue specific, and (2) most studies have not delineated the roles of the different OPN isoforms, which include intracellular versus secreted OPN and splice variants OPNa, b, and c. With this in mind, we propose to systematically investigate the role of OPN in AMD vulnerable cells with a focus on RPE biology and test the therapeutic potential of modifying OPN levels in animal models that present with dry ‘AMD-like’ pathologies. Published studies and key preliminary observations that precipitated pursuing this study include (1) circulating soluble OPN (sOPN) levels increase in a subpopulation of individuals with age; (2) the role of intracellular OPN, is less known but associated with amelioration of inflammation; (3) intracellular OPN expression in human RPE cells is decreased in early dry AMD donor tissue; (4) secreted OPN accumulates extracellularly in drusen and basal deposits of human AMD donor tissue; (5) plasma OPN is elevated in late dry AMD patients; and (6) human RPE cells secrete OPN following oxidant injury and are a potential local source. Based on our preliminary data and the known paradoxical anti- and pro-inflammatory roles of OPN in neurodegenerative and systemic diseases that share common pathogenic pathways with AMD, we will test the hypotheses that OPN regulates inflammation, aberrant RPE barrier function, and cell homeostatic mechanisms, in an isoform dependent manner.

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）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从各种因素的汇聚中出现的 流行病学、遗传学、形态学和生化研究，包括炎症、脂质 目前还没有可用的药物来治疗失调、细胞凋亡和 RPE 屏障功能障碍。 治疗干性AMD。 在本提案中，我们集中研究骨桥蛋白（OPN）的生物学和功能，骨桥蛋白是一种基质细胞 糖蛋白因其参与多种神经退行性和系统性疾病的发病机制而闻名 疾病，其中炎症是关键，部分是通过其作为巨噬细胞招募和保留的作用 然而，据报道，OPN 具有双向作用，具有促炎和抗炎特性。 此外，OPN 还被证明可以调节细胞稳态，从而影响细胞分化， 代谢、自噬、吞噬作用和细胞凋亡等这些潜在的悖论的作用。 OPN 可能部分归因于以下事实：(1) OPN 功能具有细胞和组织特异性，以及 (2) 大多数研究 尚未描述不同 OPN 亚型的作用，包括细胞内 OPN 与分泌型 OPN 考虑到这一点，我们建议系统地研究 OPNa、b 和 c 的作用。 AMD 脆弱细胞中的 OPN，重点是 RPE 生物学并测试修饰的治疗潜力 表现出干性“AMD 样”病理的动物模型中的 OPN 水平。 已发表的研究和促使开展这项研究的主要初步观察结果包括 (1) 随着年龄的增长，循环可溶性 OPN (sOPN) 水平增加； (3) 细胞内 OPN，鲜为人知，但与炎症的改善有关； 在早期干燥的 AMD 供体组织中，人 RPE 细胞的表达降低；(4) 分泌的 OPN 积累； (5)晚期血浆OPN升高 干性 AMD 患者；(6) 人类 RPE 细胞在氧化损伤后分泌 OPN，是潜在的局部细胞 来源：基于我们的初步数据以及 OPN 已知的矛盾的抗炎和促炎作用。 在与 AMD 具有共同致病途径的神经退行性疾病和系统性疾病中，我们将 检验 OPN 调节炎症、异常 RPE 屏障功能和细胞稳态的假设 机制，以异构体依赖性方式。