FGF and hyaluronan-mediated alterations in epithelial-mesenchymal transition and metabolism of RPE cells in Sorsby Fundus Dystrophy.

项目总结 索尔斯比眼底营养不良(SFD)是一种主要遗传的黄斑退行性疾病，即 以RPE营养不良和脉络膜所致的双眼中央视力丧失为特征 新生血管(CNV)。TIMP-3基因涉及外显子5或内含子4-外显子5的特异性突变 边界被证明是有因果关系的。老年性黄斑变性(AMD)联盟已经 在分析16,144名患者和17,832名对照时，发现了TIMP3基因中罕见的编码变异。这个 AMD和SFD的临床和组织病理学相似性及其变异的鉴定 AMD中的基质金属蛋白酶途径提示类似的下游效应可能在两者中起作用 条件。更好地了解SFD中CNV的病理生理机制将有助于 提供可能对AMD有用的信息。在使用TIMP-3缺陷的比较研究中 小鼠、S179CTIMP-3转基因小鼠和体外培养实验确定了RPE细胞 表达突变体TIMP3经历上皮-间充质转化(EMT)并发生改变 新陈代谢。这些变化与碱性成纤维细胞生长因子和透明质酸沉积增加有关。基于这些 结果我们假设在生理条件下，需要TIMP3来控制和定位基质 RPE/脉络膜的降解，使RPE保持在上皮性状态，并允许正常代谢 活动。TIMP3在这方面的功能丧失会导致EMT和代谢改变，这可能是 对RPE和视网膜健康有显著影响。

PROJECT SUMMARY Sorsby fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is characterized by bilateral loss of central vision as a consequence of RPE dystrophy and choroidal neovascularization (CNV). Specific mutations in the TIMP-3 gene involving exon 5 or the intron4-exon5 boundary have been shown to be causative. The age-related macular degeneration (AMD) consortium has identified rare coding variants in the TIMP3 gene when analyzing 16,144 patients and 17,832 controls. The clinical and histopathological similarities between AMD and SFD and the identification of variants in the matrix metalloproteinase pathway in AMD suggest that similar downstream effectors might be in play in both conditions. A better understanding of the pathophysiological mechanisms contributing to the CNV in SFD will provide information that could be potentially useful in AMD. In comparative studies using TIMP-3 deficient mice, S179CTIMP-3 transgenic mice and in vitro culture experiments we have determined that RPE cells expressing mutant TIMP3 undergo epithelial-mesenchymal transformation (EMT) and have altered metabolism. These changes are correlated with increased bFGF and hyaluronan deposition. Based on these results, we hypothesize that under physiological conditions, TIMP3 is required to control and localize matrix degradation in the RPE/choroid which keeps the RPE in an epithelial state and allows for normal metabolic activity. Loss of TIMP3 function in this regard leads to EMT and altered metabolism which could have significant effects on RPE and retinal health.