Mechanisms underlying the formation of the cornea and ocular surface epithelium

角膜和眼表上皮形成的机制

• 批准号: 10162603
• 负责人: Tsutomu Kume
• 金额: $ 37.89万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162603
• 关键词: Adult; Affect; Animals; Blindness; Cells; Conjunctivitis; Cornea; Corneal Neovascularization; Corneal Ulcer; Data; Defect; Development; Disease; Dose; Embryo; Epithelial; Epithelial Cells; Eye; Eye diseases; Eyelash; Eyelid structure; FOXC1 gene; FOXC2 gene; Functional disorder; Genes; Genetic; Goals; Grant; Growth; Human; Impairment; Individual; Inherited; Knock-out; Lacrimal gland structure; Lead; Limb structure; Lymphatic Obstruction; Maintenance; Matrix Metalloproteinases; Mediating; Mesenchymal; Mesenchyme; Mission; Modeling; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Neural Crest; Neural Crest Cell; Pathway interactions; Patient Care; Patients; Photophobia; Play; Public Health; Recurrence; Research; Risk; Role; Series; Severities; Structure; Surface; Symptoms; Syndrome; Testing; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vision; WNT Signaling Pathway; base; conjunctiva; corneal epithelium; experimental study; gland development; improved; insight; irritation; lymphatic drainage; lymphedema-distichiasis syndrome; meibomian gland; novel therapeutic intervention; ocular surface; targeted treatment; thrombospondin 4; treatment strategy

The ocular surface consists of a single continuous layer of epithelium and all associated structures, including the surface and glandular epithelia of the cornea, conjunctiva, and limbus, as well as the lacrimal and meibomian glands. The ocular surface plays a central role in vision, and diseases and disorders of the ocular surface and cornea is a leading cause of vision problems. The development, establishment, and maintenance of the ocular surface depend on the precise control of genetic networks that are tightly regulated by mesenchymal-epithelial interactions at the cellular level. Importantly, neural crest (NC)-derived cells give rise to the corneal and eyelid mesenchyme and are crucial for formation of the ocular surface. The long-term goal of our lab is to elucidate the fundamental mechanisms that regulate the formation and maintenance of the ocular surface and to understand how disruption of these mechanisms lead to defects in the ocular surface and cornea. Inactivating mutations of human FOXC2 are responsible for the autosomal dominant syndrome Lymphedema-distichiasis, which is characterized by the obstruction of lymphatic drainage in the limbs and the growth of aberrant, extra eyelashes (distichiasis). We have completed preliminary experiments suggesting (1) that an NC-specific mutation of Foxc2 in mice leads to corneal conjunctivalization, ectopic corneal neovascularization, defects in meibomian gland development, and impaired ocular epithelial cell identity, and (2) that compound, NC-specific mutations of Foxc2 and a closely related gene, Foxc1, have more severe eye defects, including the complete absence of the cornea, accompanied by significant declines in the expression of another key developmental factor, Pitx2, and its downstream effector Dkk2, which antagonizes canonical Wnt signaling. Thus, our central hypothesis is that Foxc2 is required in NC-derived cells for corneal development and the establishment of ocular epithelial-cell identity. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify molecular and genetic networks that govern corneal development; 2) Define the mechanisms by which Foxc2 participates in the formation of corneal epithelial-cell identity. In summary, the proposed research is significant, because our findings will contribute significantly to a better understanding of the formation of the ocular surface and the establishment of corneal epithelial identity. This will have an important positive impact on patient care, because the completion of the proposed studies will likely lead to identification of new targets and therapeutic strategies for improving vision in affected patients.

眼表由单层连续的上皮层和所有相关结构组成，包括 角膜、结膜和角膜缘的表面和腺上皮，以及泪腺和 眉板腺。眼表在视力和眼部疾病中起着中心作用 眼表和角膜是导致视力问题的主要原因。开发、建立和维护 依赖于对基因网络的精确控制，这些基因网络受到 间充质-上皮细胞水平上的相互作用。重要的是，神经沟(NC)来源的细胞产生了 角膜和眼睑间充质对眼表的形成至关重要。的长期目标是 我们的实验室是要阐明调节眼球形成和维持的基本机制。 并了解这些机制的破坏如何导致眼表和眼表的缺陷 眼角膜。人类FOXC2基因失活突变导致常染色体显性遗传综合征 淋巴水肿-二线虫病，其特征是四肢和四肢的淋巴引流受阻 异常的、多余的睫毛生长(双睫毛)。我们已经完成了初步实验，表明(1) FOXC2在小鼠中的NC特异性突变导致角膜结膜、异位角膜 新生血管、眉肌腺发育缺陷和眼上皮细胞特性受损 (2)FOXC2和一个密切相关的基因Foxc1的NC特有的复合突变会导致更严重的眼睛 缺陷，包括角膜的完全缺失，伴随着表达的显著下降 另一个关键的发育因子Pitx2及其下游效应因子Dkk2，它拮抗Canonical WNT信令。因此，我们的中心假设是角膜NC来源的细胞需要FOXC2 眼上皮细胞特性的建立和发育。在强劲的初步数据指引下，这 假说将通过追求两个具体目标来检验：1)确定支配 角膜发育；2)定义FOXC2参与角膜形成的机制 上皮细胞身份。总而言之，这项拟议的研究意义重大，因为我们的发现将有助于 对于更好地了解眼表的形成和角膜的建立具有重要意义 上皮性身份。这将对病人护理产生重要的积极影响，因为 拟议的研究可能会导致确定新的靶点和改善视力的治疗策略 在受影响的患者中。