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

项目总结/摘要 转化生长因子β（Transforming growth factor-β，TGF-β）是参与肿瘤生长的最重要的生长因子之一。 眼前节组织的形态发生，包括角膜基质、透明组织层 负责获得正常视力。我们检验了Tgfbr 2的条件性消融- 角膜基质细胞介导的信号通路可干扰出生后角膜的发育和稳态。我们 建立了一种新的Tgfbr 2角膜细胞敲除小鼠Tgfbr 2Kera-ko。这些小鼠的角膜基质 变薄表型类似于人类的圆锥角膜（KTCN），这是一种进行性眼病， 正常的圆形角膜变薄并开始凸出成锥形，导致视觉失真。我们 假设Tgfbr 2信号传导（包括Smad依赖性和/或Smad非依赖性）在 角膜细胞对于角膜形态发生和稳态是不可缺少的。Tgfbr 2Kera-ko小鼠品系是一种 TGF-β信号通路及其下游信号通路的分子机制 用于角膜发育和稳态的角膜细胞中的靶点。据我们所知，这种小鼠品系可能 成为人类KC研究和治疗的第一个遗传定义的动物模型。我们提出两个具体目标， 实现这些目标。 具体目标1：阐明Tgfbr 2介导的信号传导在间充质角膜细胞中的作用 角膜发育和体内平衡。 具体目标2：明确Tgfbr 2信号通路的Smad依赖性或非Smad途径 在角膜细胞中发生，以调节角膜发育和体内平衡。 影响：在两年内完成这些拟议目标将提供有关 TGF-β信号在角膜发育和稳态过程中在间充质角膜细胞中的关键作用- 作为改善眼睛护理和相关眼病如角膜炎的长期目标的基础， 扩张（圆锥角膜）。在更大的范围内，从角膜获得的信息可以被利用在 其他组织系统，其中间充质TGF-β信号传导对于发育、稳态和 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.