Mechanisms of anterior segment development and corneal neovascularization

描述（由申请方提供）：使用小鼠进行的分子和遗传研究表明，神经嵴衍生细胞产生小梁网以及角膜基质和内皮，并且对于眼前段的形成至关重要。人类眼前节正常发育的失败导致成熟眼前节结构的异常，与青光眼和角膜混浊的风险增加相关。 转录因子Foxc 1在发育中的眼睛周围的神经嵴和中胚层来源的眼周间充质中表达。我们以前已经表明，杂合和纯合的Foxc 1无效突变小鼠有许多眼部异常，包括缺乏前房和角膜内皮，虹膜营养不良和小梁网异常。人类FOXC 1的突变与常染色体显性Axenomal-Rieger综合征（ARS）相关，ARS是一种以眼前节缺损、青光眼和其他眼外异常为特征的疾病。Foxc 2是一种密切相关的因子，在神经嵴衍生的眼周间充质中表达，Foxc 2杂合子和复合Foxc 1; Foxc 2杂合子突变小鼠具有与Foxc 1杂合子突变小鼠相似的缺陷，如虹膜异常。然而，Foxc 2/FOXC 2相对于Foxc 1/FOXC 1在眼前节发育中的确切作用仍然未知。 我们的新数据让中心的假设，Foxc 1和Foxc 2有重叠，以及不同的作用，在发展中的眼前段的眼睛和角膜无血管。该假设将通过以下方式进行检验：（1）分析一系列神经嵴和中胚层特异性Foxc突变体以及Foxc 2敲入小鼠中眼前段的形成，（2）阐明一系列神经嵴和中胚层特异性Foxc突变体以及Foxc 2敲入小鼠中的角膜NV，以及（3）定义Foxc突变角膜角膜基质细胞的血管生成特性。 成功完成拟议的实验将提供有价值的见解的重叠和独特的作用，Foxc 1和Foxc 2在眼前段的发展和角膜无血管性和基本机制，导致发展的治疗策略，旨在抑制角膜NV。 公共卫生相关性：遗传性眼前节疾病在人类中很常见，但其原因和潜在的发育机制知之甚少。显然，突变小鼠提供了有用的模型来阐明眼前节发育和发育不全以及角膜新生血管的分子和细胞机制。拟议的研究将大大有助于更好地了解与眼前段相关的先天性缺陷的原因，并深入了解相关人类疾病的细胞和分子基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Inherited disorders of the anterior segment of the eye are common in humans, but their causes and underlying developmental mechanisms are poorly understood. It is clear that mutant mice provide useful models to elucidate the molecular and cellular mechanisms of anterior segment development and dysgenesis as well as corneal neovascularization. The proposed studies will significantly contribute to a better understanding of the causes of congenital defects associated with the anterior segment of the eye and gain insight into the cellular and molecular basis of related human diseases.