REPAIR AND REGENERATION IN THE CORNEAL STROMA

描述（由申请人提供）：角膜将光线聚焦在视网膜上，提供眼睛三分之二以上的屈光力。为了实现这一功能，它必须是完全透明的，并且必须具有精确的形状，这是在胚胎发育期间实现的。成年人的角膜似乎有多种机制来保持良好的状态，我们在当前项目期间将这组现象定义为“角膜恒常性”。当角膜损伤足够广泛时，角膜稳定性可以被克服，并随之产生修复反应。角膜的修复质量存在于一个范围内，一端的修复过程几乎是完全再生的，而另一端则是纤维化修复。在角膜中，纤维化造成混浊，纤维化修复组织的收缩改变了角膜形状。这些影响对视网膜折射光线的能力产生了不利的影响。该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。在过去的十年中，该研究小组和其他研究人员已经建立了一种纤维化进展的模型，该模型是一个两步过程，当角化细胞被“激活”时开始，假设为“成纤维细胞”表型，可进展为与纤维化修复相关的“肌成纤维细胞”表型。对一些决定激活和进展的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化组织修复之间的重要差异。在新的项目期间，该小组建议对这些关键发现进行后续研究，目标是临床应用。这两个目标解决以下问题：1)角质细胞活化和角膜晶体转酮醇酶丧失的机制，这对细胞透明度很重要；2)向纤维化的转变以及角膜上皮基底膜决定纤维化调节因子tgf - β 2释放的机制。目前，角膜屈光矫正围绕着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也可以改善手术结果。该小组将专注于有望为药物干预的分子靶点提供新见解的问题。

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.