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

项目摘要 Sorsby眼底营养不良（SFD）是一种显性遗传性黄斑变性疾病， 其特征在于作为RPE营养不良和脉络膜视网膜变性的结果的双侧中心视力丧失。 新生血管形成（CNV）。TIMP-3基因中涉及外显子5或内含子4-外显子5的特异性突变 边界已被证明是因果关系。年龄相关性黄斑变性（AMD）协会 在分析16,144名患者和17,832名对照时，发现了TIMP 3基因中的罕见编码变异。的 AMD和SFD之间的临床和组织病理学相似性，以及 基质金属蛋白酶途径提示，类似的下游效应物可能在两种疾病中起作用。 条件更好地理解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、S179 CTIMP-3转基因小鼠和体外培养实验中，我们已经确定RPE细胞 表达突变型TIMP 3的细胞经历上皮-间充质转化（EMT）， 新陈代谢.这些变化与bFGF和透明质酸沉积增加相关。基于这些 结果，我们假设在生理条件下，TIMP 3需要控制和定位基质， RPE/脉络膜中的降解，其保持RPE处于上皮状态并允许正常的代谢 活动在这方面，TIMP 3功能的丧失导致EMT和代谢改变，这可能导致 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.