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

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)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从各种不同的 流行病学、遗传学、形态学和生化研究，包括炎症、血脂 调节失调、细胞凋亡和RPE屏障功能障碍等。目前还没有可用的药物。 治疗干性AMD。 在这项建议中，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 糖蛋白参与多种神经退行性变和全身性疾病的发病机制 疾病，其中炎症是关键，部分是通过其作为巨噬细胞募集和滞留的作用 因素。然而，据报道，OPN具有双面作用，既有促炎作用，也有抗炎作用。 此外，OPN还被证明调节细胞内稳态，影响细胞分化， 新陈代谢、自噬、吞噬和细胞凋亡等等。这一潜在的悖论在 OPN的部分原因可能是(1)OPN的功能是细胞和组织特有的，以及(2)大多数研究 还没有描述不同的OPN亚型的作用，包括细胞内和分泌的OPN 和剪接变异体OPNa，b和c。考虑到这一点，我们建议系统地研究 OPN在AMD易损细胞中的作用，重点研究RPE生物学和检测修饰的治疗潜力 出现干性AMD样病理的动物模型中的OPN水平。 推动这项研究的已发表研究和关键初步观察包括(1) 循环中的可溶性骨桥蛋白(SOPN)水平随年龄增长而增加；(2) 细胞内OPN，知之甚少，但与减轻炎症有关；(3)细胞内OPN 早期干性AMD供体组织中人RPE细胞表达减少；(4)分泌的OPN积聚 (5)晚期血浆骨桥蛋白水平升高。 干性AMD患者；(6)人RPE细胞在氧化损伤后分泌OPN，是潜在的局部 消息来源。基于我们的初步数据和已知的OPN矛盾的抗炎和促炎作用 在与AMD有共同致病途径的神经退行性和全身性疾病中，我们将 验证OPN调节炎症、异常RPE屏障功能和细胞内环境平衡的假说 机制，以异构体依赖的方式。

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.