Investigating the Action and Physiological Role of Slc4a11 in the Cornea

项目摘要/摘要 Fuchs内皮性角膜营养不良(FECD)是导致视力丧失的主要原因，也是 角膜移植。一个健康的角膜内皮细胞层将液体从角膜基质中泵出以维持 角膜透明的最佳水化状态。迟发性FECD是由内皮功能丧失引起的 并与包括SLC4A11在内的几个基因突变的显性遗传有关。SLC4A11编码一个 内皮H+转运蛋白。为老年人开发非侵入性治疗以预防或延迟 FECD的发病将消除移植的需要。然而，治疗进展受到了一种 缺乏对这种复杂疾病发生的分子机制的了解，以及缺乏 适合和多样化的动物模型，用于开发和测试疗法。为了解决这两个问题，转基因 已经产生了携带主要人类FECD突变体Trp240Ser(W240S)的鼠系 SLC4A11基因。W240S杂合子小鼠出现浮肿和抗氧化能力降低的迹象，但没有 诊断胶。这项研究的假设是，这些小鼠更容易受到氧化应激和 将模拟UVA-光暴露的FECD。有两个目的[1]检查分子后果 W240S突变对内皮细胞健康的影响。[2]研究SLC4A11突变与表型的关系。这个 拟议中的研究既有意义又有创新，因为它是第一个重新创造符号的遗传小鼠模型 并使用新的工具和多学科的方法，将为制定 FECD的新的早期诊断、风险评分和治疗方法。

Project Summary/Abstract Fuchs Endothelial Corneal Dystrophy (FECD) is a major cause of vision loss and a leading indication for corneal transplantation. A healthy corneal endothelial cell layer pumps fluid out of the corneal stroma to maintain the optimal hydration state for corneal transparency. Late-onset FECD is caused by loss of endothelial function and is linked to dominant inheritance of mutations in several genes including SLC4A11. SLC4A11 encodes an endothelial H+ transporter. The development of non-invasive therapies for older individuals to prevent or delay FECD onset would obviate the need for transplants. However, therapeutic advances have been hindered by a lack of understanding of the molecular mechanisms that underlie onset of this complex disease and a lack of suitable and diverse animal models for developing and testing therapies. To address both issues, a transgenic mouse-line has been generated that carries the dominant human FECD mutant Trp240Ser (W240S) in its SLC4A11 gene. W240S heterozygous mice develop edema and signs of reduced antioxidant capacity, but not diagnostic guttae. The hypothesis of this study is that these mice are more susceptible to oxidative stress and will model FECD upon UVA-light exposure. There are two aims [1] Examine the molecular consequences of the W240S mutation on endothelial health. [2] Examine the link between SLC4A11 mutation and phenotype. The proposed research is both significant and innovative because it the first genetic mouse model that recreate signs of late-onset FECD and uses novel tools and a multidisciplinary approach that will inform the development of new early-diagnostic, risk-scoring, and therapeutic approaches for FECD.