Mechanisms of anterior segment development and corneal neovascularization

描述(申请人提供)：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形成小梁网以及角膜的基质和内皮，对眼睛前段的形成至关重要。人类眼球前段的正常发育失败会导致成熟的前段结构异常，与青光眼和角膜混浊的风险增加相关。转录因子Foxc1在发育中眼周围的神经脊和中胚层来源的眼周间充质中表达。我们先前已经证明，Foxc1杂合子和纯合子缺失突变小鼠有大量的眼部异常，包括前房和角膜内皮的缺失，虹膜营养不良和小梁网的异常。人类FOXC1基因突变与常染色体显性遗传的阿森菲尔德-里格综合征(ARS)有关，ARS是一种以眼前节缺陷、青光眼和其他眼外异常为特征的疾病。FOXC2是一种密切相关的因子，表达于神经脊来源的眼周间充质、FOXC2杂合子和复合Foxc1；FOXC2杂合子突变小鼠与Foxc1杂合子突变小鼠具有类似的虹膜异常等缺陷。然而，FOXC2/FOXC2相对于Foxc1/FOXC1在眼前段发育过程中的确切作用仍不清楚。我们的新数据支持这一中心假设，即Foxc1和FOXC2在眼前节和角膜无血管的发育过程中既有重叠又有不同的作用。为验证这一假设，将进行以下工作：(1)分析一系列神经脊和中胚层特异的Foxc突变体以及FOXC2敲入鼠的眼前段形成过程；(2)检测一系列神经脊和中胚层特异的Foxc突变体和FOXC2敲入鼠的角膜NV；以及(3)确定FOXC突变型角膜基质细胞的血管生成特性。拟议实验的成功完成将为了解Foxc1和FOXC2在眼前段发育和角膜无血管中重叠和独特的作用以及导致开发旨在抑制角膜NV的治疗策略的基本机制提供宝贵的见解。 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尚不清楚。显然，突变小鼠为阐明眼前段发育和发育不全以及角膜新生血管的分子和细胞机制提供了有用的模型。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.