Investigating the Action and Physiological Role of Slc4a11 in the Cornea

项目总结/摘要 Fuchs内皮角膜营养不良（FECD）是视力丧失的主要原因，也是 角膜移植健康的角膜内皮细胞层将液体从角膜基质中泵出，以维持角膜内皮细胞的生长。 角膜透明的最佳水合状态。迟发性FECD由内皮功能丧失引起 并且与包括SLC 4A 11在内的几个基因中的突变的显性遗传有关。SLC 4A 11编码一种 内皮H+转运蛋白。为老年人开发非侵入性疗法，以预防或延迟 FECD发作会导致需要移植。然而，治疗进展受到了 缺乏对这种复杂疾病发病的分子机制的了解， 用于开发和测试疗法的合适且多样的动物模型。为了解决这两个问题，转基因 已经产生了小鼠系，其在其细胞中携带显性人FECD突变体Trp 240 Ser（W240 S）。 SLC 4A 11基因。W240 S杂合子小鼠出现水肿和抗氧化能力降低的迹象，但没有 诊断用滴眼液这项研究的假设是，这些小鼠更容易受到氧化应激， 将在UVA光暴露后模拟FECD。有两个目标[1]检查的分子后果的 W240 S突变对内皮健康的影响[2]检查SLC 4A 11突变和表型之间的联系。的 这项研究既有意义又有创新性，因为它是第一个重现体征的遗传小鼠模型。 并使用新的工具和多学科的方法，将告知发展 新的早期诊断，风险评分和FECD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.