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

Tgf-β-信号在角膜发育和疾病中的作用

基本信息

批准号：
10254192
负责人：
CHIA-YANG LIU
金额：
$ 9.01万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254192
关键词：
ARHGEF5 gene Ablation Adult Animal Model Anterior Anterior segment dysgenesis Basal Cell Bilateral Biochemical Caring Cell Differentiation process Cell Proliferation Cells Cone Cornea Corneal Diseases Corneal Stroma Defect Descemet&apos s membrane Development Disease Edema Embryo Epithelial Etiology Eye Eye Development Eye diseases Functional disorder Future Genes Genetic Goals Growth Growth Factor Histologic Homeostasis Human Intervention Keratoconus Knockout Mice Knowledge Link Maintenance Mechanics Mediating Mesenchymal Modeling Molecular Molecular Target Morphogenesis Morphology Mouse Strains Mus Neural Crest Cell Pathogenesis Pathological Dilatation Pathway interactions Perforation Perinatal mortality demographics Phenotype Physiology Proto-Oncogene Proteins c-abl Research Role Shapes Signal Pathway Signal Transduction Structure System TGF Beta Signaling Pathway Techniques Thick Thinness Tissues Transforming Growth Factor Beta 2 Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Vision base genomic RNA human disease improved in vivo malformation neonate novel novel therapeutics postnatal pup receptor transcriptome sequencing wound healing

项目摘要

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.

项目概要/摘要转化生长因子-β (TGF-β) 是参与细胞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）我们检验了 Tgfbr2- 条件性消融的假设。角膜细胞介导的信号通路可能会扰乱出生后角膜的发育和稳态。产生了一种新型 Tgfbr2 角膜细胞敲除小鼠，Tgfbr2Kera-ko 这些小鼠表现出严重的角膜基质病变。人类中类似于圆锥角膜（KTCN）的变薄表型，这是一种进行性眼病，其中通常圆形的角膜变薄并开始凸出成圆锥形，导致视力扭曲。强化了 Tgfbr2 信号传导（包括 Smad 依赖性和/或 Smad 独立性） Tgfbr2Kera-ko 小鼠品系是角膜形态发生和稳态不可缺少的细胞。阐明TGF-β信号通路及其下游分子机制的潜在模型据我们所知，这种小鼠品系可能是角膜细胞中角膜发育和稳态的靶标。成为第一个用于人类 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。实现这些目标。具体目标 1：阐明 Tgfbr2 介导的信号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：找出 Tgfbr2 信号传导所通过的 Smad 依赖或非 Smad 途径发生在角膜细胞中，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以下方面的开创性知识：间充质角膜细胞中 TGF-β 信号传导在角膜发育和稳态过程中的关键作用作为改善眼部护理和角膜等相关眼部疾病的长期目标的基础在更大范围内，可以利用从角膜获得的信息来治疗角膜扩张（圆锥角膜）。其他组织系统，其中间充质 TGF-β 信号传导对于发育、体内平衡和生长至关重要伤口愈合。