Mechanisms of anterior segment development and corneal neovascularization

项目摘要 用小鼠进行的分子和遗传学研究表明，神经脊来源的细胞可以产生 小梁网以及角膜的基质和内皮是至关重要的。 用于形成眼球的前段。人类正常发展的一次失败 人类眼睛的前段导致成熟的前部结构异常 与青光眼和角膜混浊的风险增加有关。 转录因子foxc1在神经脊和中胚层表达 发育中眼球周围的间质组织。我们之前已经表明， Foxc1杂合和纯合子缺失突变小鼠有大量的眼睛 异常，包括前房和角膜内皮缺乏，虹膜营养不良 小梁网异常。人类FOXC1基因突变与 常染色体显性AXENFELD-Rieger综合征(ARS)，一种以前路为特征的疾病 节段性缺陷、青光眼和其他眼外异常。FOXC2，一个密切相关的因素，是 在神经沟来源的眼周间充质中表达，以及FOXC2杂合子和 复合Foxc1；FOXC2杂合突变小鼠有类似的虹膜等缺陷 Foxc1杂合突变体的异常。然而，它的确切作用是 Foxc2/FOXC2相对于Foxc1/FOXc1在眼前段发育过程中仍然存在 未知。 我们的新数据支持了一个中心假设，即Foxc1和FOXC2也存在重叠 在眼球前段的发育和角膜无血管中起着不同的作用。 这一假设将通过以下方式得到验证：(1)分析眼球前段的形成 在一系列神经脊和中胚层特异的FOXC突变体以及FOXC2敲入中 小鼠，(2)在一系列神经脊和中胚层特异的Foxc中阐明角膜NV 突变体和FOXC2敲入小鼠，以及(3)确定Foxc-1的血管生成特性。 突变的角膜基质细胞。 成功完成拟议的实验将提供宝贵的洞察 Foxc1和FOXC2在眼前段发育和角膜发育中的重叠和独特作用 无血管和进入导致治疗的发展的基本机制 旨在抑制角膜NV的策略。

Project Summary Molecular and genetic studies using mice show that neural crest-derived cells give rise to the trabecular meshwork as well as the stroma and endothelium of the cornea and are critical for the formation of the anterior segment of the eye. A failure of the normal development of the anterior segment of the eye in humans leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. The transcription factor Foxc1 is expressed in neural crest- and mesoderm-derived periocular mesenchyme surrounding the developing eye. We have previously shown that heterozygous and homozygous null mutant mice for Foxc1 have numerous ocular abnormalities, including lack of the anterior chamber and corneal endothelium, iris dystrophy and abnormalities of the trabecular meshwork. Mutations in human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma and other extraocular anomalies. Foxc2, a closely related factor, is expressed in neural crest-derived periocular mesenchyme, and Foxc2 heterozygous and compound Foxc1; Foxc2 heterozygous mutant mice have similar defects such as iris abnormalities to those in Foxc1 heterozygous mutants. However, the exact role of Foxc2/FOXC2 with respect to Foxc1/FOXC1 during anterior segment development is still unknown. Our new data let to the central hypothesis that Foxc1 and Foxc2 have overlapping as well as distinct roles in development of the anterior segment of the eye and corneal avascularity. This hypothesis will be tested by: (1) analyzing the formation of the anterior segment of the eye in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, (2) elucidating corneal NV in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, and (3) defining the angiogenic properties of Foxc- mutant corneal keratocytes. Successful completion of the proposed experiments will provide valuable insight into the overlapping and unique roles of Foxc1 and Foxc2 in anterior segment development and corneal avascularity and into the fundamental mechanisms that lead to the development of therapeutic strategies designed to inhibit corneal NV.