Role of Tgf-beta-signaling in corneal development and diseases

项目摘要/摘要 转化生长因子-β(转化生长因子-β)是最重要的生长因子之一。 包括透明组织层角膜基质在内的眼前段组织的形态发生 负责获得正常视力。我们检验了TGFBR2条件消融的假设- 角膜基质细胞中介导的信号通路可以干扰出生后角膜的发育和动态平衡。我们 产生了一种新的TGFBR2角质细胞基因敲除小鼠Tgfbr2Kera-Ko。这些小鼠表现出严重的角膜基质。 人类类似圆锥角膜的变薄表型(KTCN)，一种进行性眼病，在这种疾病中 正常情况下，圆形角膜变薄，并开始鼓起成锥形，导致视力扭曲。我们 假设TGFBR2信令(包括Smad依赖和/或Smad非依赖)在 角膜基质细胞是角膜形态发生和动态平衡不可缺少的细胞。Tgfbr2Kera-Ko小鼠品系是一种 潜在模型解释转化生长因子-β信号通路及其下游的分子机制 角膜基质细胞中促进角膜发育和动态平衡的靶点(S)。据我们所知，这种老鼠品系可能 成为首个用于人类KC研究和治疗的基因定义动物模型。我们提出了两个具体目标来 实现这些目标。 具体目的1：阐明TGFBR2介导的信号转导在间质角质形成细胞中的作用 角膜发育和动态平衡。 具体目标2：找出TGFBR2信号通过Smad依赖或非Smad途径 发生在角膜基质细胞中，以调节角膜发育和动态平衡。 影响：在两年内完成这些拟议目标将提供有关 转化生长因子-β信号在角膜间充质细胞发育和动态平衡中的重要作用 作为改善眼睛护理和相关眼部疾病(如角膜)的长期目标的基础 扩张症(圆锥角膜)在更大的范围内，从角膜获得的信息可以被利用 间充质转化生长因子-β信号对发育、动态平衡和 伤口愈合。

PROJECT SUMMARY/ABSTRACT Transforming growth factor-beta (TGF-β) is one of the most important growth factors involved in morphogenesis of ocular anterior segment tissues including corneal stroma, a transparent tissue layer responsible for acquiring normal vision. We examined the hypothesis that conditional ablation of Tgfbr2- mediated signaling pathway in keratocytes can perturb postnatal corneal development and homeostasis. We generated a novel Tgfbr2 keratocyte knockout mice, Tgfbr2Kera-ko. These mice display a severe corneal stromal thinning phenotype resembling keratoconus (KTCN) in humans, a progressive eye disease in which the normally round cornea thins and begins to bulge into a cone-like shape causing distorted vision. We hypothesize that the Tgfbr2 signaling (including Smad-dependent and/or Smad-independent) in keratocytes is indispensable for corneal morphogenesis and homeostasis. Tgfbr2Kera-ko mouse strain is a potential model to elucidate the molecular mechanism of TGF-β signaling pathway and its downstream target(s) in keratocytes for corneal development and homeostasis. To our knowledge, this mouse strain may be the first genetic-defined animal model for human KC research and therapy. We propose two specific aims to achieve these goals. Specific Aim 1: To elucidate the role of Tgfbr2-mediated signaling in mesenchymal keratocytes during corneal development and homeostasis. Specific Aim 2: To figure out the Smad-dependent or non-Smad pathway through which Tgfbr2 signaling takes place in the keratocyte to regulate corneal development and homeostasis. Impact: Completion of these proposed aims in two years will provide groundbreaking knowledge regarding the critical roles of TGF-β signaling in mesenchymal keratocytes during corneal development and homeostasis- serving as the basis for the long term goal of improving eye care and related ocular diseases like corneal ectasia (keratoconus). On an even greater scale, the information gained from the cornea can be harnessed in other tissue systems where mesenchymal TGF-β signaling is crucial for development, homeostasis, and wound healing.