REPAIR AND REGENERATION IN THE CORNEAL STROMA

描述(申请人提供)：角膜将光线聚焦在视网膜上，提供超过眼睛三分之二的屈光力。要执行这一功能，它必须是完全透明的，并且必须有一个精确的形状，在胚胎发育期间实现。成人的角膜似乎有多种机制，可以让一件好的东西足够好地留在一边，这是我们在当前项目期间定义的一组现象，称为“角膜恒定”。当对角膜的损伤足够大时，角膜的恒定性可以被克服，修复反应随之而来。角膜修复的质量在光谱上存在，一端的修复过程几乎完全再生，而另一端的修复过程是纤维性修复。在角膜中，纤维化会造成混浊，纤维化修复组织的收缩会改变角膜的形状。这些影响会对视网膜折射光线的能力造成不良影响。这个项目的长期目标是提高我们对角膜停滞、修复反应和赋予再生特性的机制的理解。在过去的十年里，这个研究小组和其他人建立了一个纤维化进展的模型，这个模型是一个两步过程，从角质形成细胞被“激活”开始，呈现出“成纤维细胞”的表型，这种表型可以发展成与纤维化修复相关的“肌成纤维细胞”表型。对决定激活和进展的一些分子机制也有了深入的了解。此外，这个实验室小组已经确定了角膜修复和血管组织修复之间的重要区别。在新的项目期间，该小组建议对其中一些关键发现进行跟踪，以实现临床应用的目标。这两个目标涉及以下两个目标：1)角膜上皮细胞的激活和对细胞透明度至关重要的角膜晶体转酮醇酶的丢失机制；2)向纤维化的转变和角膜上皮基底膜决定纤维化调节因子转化生长因子-β2释放的机制。目前，角膜屈光矫正的核心是手术技术的日益完善，以限制伤口修复反应的数量。然而，可以认为，通过控制修复质量，手术结果也可能得到改善。该小组将专注于有望为药物干预提供新的分子靶点的问题。

DESCRIPTION (provided by applicant): The cornea focuses light on the retina, providing more than two thirds the refractive power of the eye. To perform this function, it must be completely transparent, and it must have a precise shape, achieved during embryonic development. The adult cornea appears to have multiple mechanisms for leaving a good thing well enough alone, a group of phenomena we defined in the current project period as "corneal constancy". When damage to the cornea is extensive enough, corneal constancy can be overcome, and a repair response ensues. The quality of repair in the cornea exists on a spectrum, with the process at one end being almost completely regenerative while at the opposite end is fibrotic repair. In the cornea, fibrosis creates opacity, and the contraction of fibrotic repair tissue alters corneal shape. These effects impinge undesirably on the capacity to refract light on the retina. The long-term goal of this project is to improve our understanding of corneal stasis, the repair response, and the mechanisms that confer regenerative character. Over the past decade, this research group and others have developed a model for fibrotic progression as a two step process that begins when keratocytes are "activated", assuming a "fibroblast" phenotype, which can progress to the "myofibroblast" phenotype associated with fibrotic repair. Insight has also been acquired into some of the molecular mechanisms determining activation and progression. Moreover, this lab group has identified important differences between corneal repair and repair in vascularized tissues. In the new project period, the group proposes to follow up on some of these key findings with the goal of clinical application. The two aims address the following: 1) keratocyte activation and the mechanisms for loss of the corneal crystalline transketolase, important for cell transparency; 2) transition to fibrosis and the mechanism whereby the corneal epithelial basement membrane determines release of the fibrotic regulator TGF-beta2. At the present time, corneal refractive correction revolves around the increasing refinement of surgical technique to limit the quantity of the wound repair response. However, it could be argued that surgical outcomes might also be improved by controlling the quality of repair. The group will focus on questions that promise to provide new insight into molecular targets for pharmacologic intervention.