Mechanisms of anterior segment development and corneal neovascularization

人类眼前段发育异常(眼前段发育不良；ASD)导致 结构异常，并与青光眼和角膜混浊的风险增加有关。突变或 人类FOXC1基因拷贝数的改变与常染色体显性AXENFELD-Rieger相关 综合征(ARS)，一种以眼前段缺陷、青光眼和其他眼外疾病为特征的疾病 反常现象。我们最近发现，ARS也与角膜新生血管有关，这是一种现象- 由病理性血管生成引起的威胁状态。我们实验室的长期目标是了解 调节角膜血管生长和前段发育的基本机制。这个 此更新应用的目的是研究转录因子Foxc1和FOXC2在前角蛋白中的作用。 在发育性和病理性角膜新生血管和角膜中的节段发育 结晶化。我们最近发现，小鼠NC系细胞中Foxc1的失活会导致 类似于ARS相关ASD患者的眼前段缺陷，类似于 常规Foxc1突变胚胎，包括伴有异常形成的角膜新生血管 角膜基质中的细胞外基质。我们还完成了初步实验，表明(1) 密切相关基因FOXC2的NC特异性突变导致角膜异位新生血管 以及受损的眼上皮细胞识别和角膜结膜；(2)该化合物，NC- 特定的Foxc1；FOXC2突变体有更严重的眼睛缺陷，包括完全没有角膜，以及 (3)眼部缺陷的严重程度与基因剂量相关。因此，我们的中心假设是Foxc1 和FOXC2是眼睛发育和角膜无血管所必需的。在强劲的初步数据指引下，这 将通过追求三个具体目标来检验假设：1)确定是否需要Foxc1和FOXC2 2)阐明Foxc1和FOXC2是否是眼睛发育所必需的 在发育期间和成年动物中维持角膜无血管；以及3)通过以下方式确定机制 哪些Foxc1和FOXC2参与了角膜新生血管的形成和维持 上皮细胞身份。这种方法是创新的，因为该提案包含了创新的概念和 了解先天性眼病和病理性角膜病变发生发展的途径 Foxc1和FOXC2在不同血统的细胞中的表达调控着新生血管的形成。在……里面 综上所述，拟议的研究具有重要意义，因为我们拟议的研究的完成将 在医学和分子生物科学领域都做出了重大贡献。我们希望我们的发现能有 对患者护理产生了重要的积极影响，因为对眼睛这些基本机制的了解 角膜的发育和维护可能会导致新的治疗策略，以预防和 治疗眼科疾病。

Abnormal development of the anterior segment in humans (anterior segment dysgenesis; ASD) leads to structural anomalies and is associated with an increased risk of glaucoma and corneal opacity. Mutations or changes in the copy number of human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma, and other extraocular anomalies. We have recently shown that ARS is also associated with corneal neovascularization, a sight- threatening condition caused by pathological angiogenesis. The long-term goal of our lab is to understand the fundamental mechanisms that regulate corneal vessel growth and anterior-segment development. The objective of this renewal application is to study the role of the transcription factors Foxc1 and Foxc2 in anterior segment development, in both developmental and pathological corneal neovascularization, and in corneal conjuctivalization. We have recently shown that inactivation of Foxc1 in the NC-lineage cells of mice leads to anterior-segment defects that are analogous to those in patients with ARS-related ASD and similar to those in conventional Foxc1 mutant embryos, including corneal neovascularization accompanied by aberrant formation of extracellular matrix in the corneal stroma. We have also completed preliminary experiments suggesting (1) that an NC-specific mutation in a closely related gene, Foxc2, leads to ectopic neovascularization in the cornea as well as impaired ocular epithelial cell identity and corneal conjunctivalization; (2) that compound, NC- specific Foxc1; Foxc2 mutants have more severe eye defects, including complete absence of the cornea, and (3) that the severity of the ocular defects is gene-dose dependent. Thus, Our central hypothesis is that Foxc1 and Foxc2 are required for eye development and corneal avascularity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine whether Foxc1 and Foxc2 are required in NC-lineage cells for early eye development; 2) Elucidate whether Foxc1 and Foxc2 are essential for maintaining corneal avascularity during development and in adult animals; and 3) Define the mechanisms by which Foxc1 and Foxc2 participate in corneal neovascularization and in the establishment and maintenance of epithelial-cell identity. The approach is innovative, because the proposal comprises innovative concepts and approaches to understanding how the development of congenital eye disorders and pathological corneal neovascularization are regulated by the expression of Foxc1 and Foxc2 in cells from a variety of lineages. In summary, the proposed research is significant, because the completion of our proposed research will contribute significantly to the fields of both medicine and molecular bioscience. We expect our findings to have an important positive impact on patient care, because knowledge of these fundamental mechanisms of ocular development and corneal maintenance will likely to lead to new therapeutic strategies for the prevention and treatment of ocular disorders.