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

FGF 和透明质酸介导的索斯比眼底营养不良中 RPE 细胞上皮-间质转化和代谢的改变。

• 批准号: 10408757
• 负责人: BELA ANAND-APTE
• 金额: $ 62.17万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408757
• 关键词: Age; Age related macular degeneration; Apical; Automobile Driving; Autopsy; Behavior; Bilateral; Blindness; Cells; Cessation of life; Characteristics; Choroid; Choroidal Neovascularization; Citric Acid Cycle; Clinical; Code; Comparative Study; Data; Defect; Degenerative Disorder; Deposition; Development; Disease; Disease model; Elements; Endothelium; Epithelial; Exons; Extracellular Matrix; FGF2 gene; Fibroblast Growth Factor; Fibrosis; Functional disorder; Funding; Genes; Health; Hereditary Disease; Human; Hyaluronan; In Vitro; Inherited; Knowledge; Lead; Literature; Macular degeneration; Matrix Metalloproteinases; Mediating; Mesenchymal; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mutation; Nutrient; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Penetrance; Photoreceptors; Physiological; Physiology; Play; Proteomics; Retina; Role; Sorsby' s fundus dystrophy; Structure of retinal pigment epithelium; TIMP3 gene; Testing; Tissues; Transgenic Mice; Variant; Vision; base; disease-causing mutation; experimental study; in vivo; in vivo Model; inhibitor; macula; macular dystrophy; metabolomics; multiple omics; mutant; new therapeutic target; novel; novel therapeutic intervention; transcriptome sequencing; uptake

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.

项目摘要 索斯比眼底营养不良（SFD）是一种主要遗传的黄斑的退化性疾病 由于RPE营养不良和脉络膜而导致双侧丧失中央视力的特征 新血管形成（CNV）。 TIMP-3基因中涉及外显子5或内含子4-Exon5的特异性突变5 边界已被证明是病因。与年龄相关的黄斑变性（AMD）财团具有 分析16,144例患者和17,832例对照时，在Timp3基因中确定了罕见的编码变体。这 AMD和SFD之间的临床和组织病理学相似性以及鉴定变体 AMD中的基质金属蛋白酶途径表明，类似的下游效应子可能在两者中发挥作用 状况。更好地理解有助于SFD中CNV的病理生理机制 提供可能在AMD中有可能有用的信息。在使用TIMP-3缺乏的比较研究中 小鼠，S179CTIMP-3转基因小鼠和体外培养实验我们已经确定RPE细胞 表达突变的timp3发生上皮 - 间质转化（EMT），并改变了 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，timp3需要控制和定位矩阵 RPE/脉络膜中的降解，使RPE保持上皮状态并允许正常代谢 活动。在这方面，timp3功能的丧失会导致EMT和新陈代谢改变，这可能具有 对RPE和视网膜健康的重大影响。