Mechanisms underlying the formation of the cornea and ocular surface epithelium

角膜和眼表上皮形成的机制

基本信息

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
项目类别：
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

项目摘要

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.

眼表面由单个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，以及泪腺和睑板腺。眼表在视力、眼部疾病和紊乱中起着核心作用表面和角膜是视力问题的主要原因。开发、建立、维护眼表的变化取决于遗传网络的精确控制，而遗传网络受到严格调控细胞水平上的间充质-上皮相互作用。重要的是，神经嵴（NC）来源的细胞产生角膜和眼睑间质，对于眼表的形成至关重要。长期目标是我们的实验室旨在阐明调节眼部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缺陷角膜。人类 FOXC2 失活突变导致常染色体显性综合征淋巴水肿-双歧病，其特征是四肢和淋巴回流受阻异常的多余睫毛生长（双睫）。我们已经完成了初步实验建议（1）小鼠 Foxc2 的 NC 特异性突变导致角膜结膜化、异位角膜新血管形成、睑板腺发育缺陷和眼上皮细胞特性受损，以及 (2) Foxc2 和密切相关的基因 Foxc1 的复合 NC 特异性突变会导致更严重的眼病缺陷，包括角膜完全缺失，并伴有表达显着下降另一个关键的发育因子 Pitx2 及其下游效应子 Dkk2，它对抗典型的 Wnt 信号传导。因此，我们的中心假设是，角膜的 NC 衍生细胞需要 Foxc2 眼上皮细胞身份的发育和建立。在强有力的初步数据的指导下，假设将通过追求两个具体目标来检验：1）识别控制的分子和遗传网络角膜发育； 2) 明确Foxc2参与角膜形成的机制上皮细胞身份。总之，拟议的研究意义重大，因为我们的发现将有助于显着有助于更好地了解眼表的形成和角膜的建立上皮身份。这将对患者护理产生重要的积极影响，因为完成拟议的研究可能会导致确定改善视力的新靶点和治疗策略在受影响的患者中。