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: 9910411
• 负责人: Tsutomu Kume
• 金额: $ 39.09万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910411
• 关键词: Adult; Affect; Animals; Blindness; Cells; Conjunctivitis; Cornea; Corneal Neovascularization; Corneal Ulcer; Data; Defect; Development; Disease; Dose; Embryo; Epithelial; Epithelial Cells; Epithelium; 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; Lymphedema; 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; 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.

眼表由单层连续上皮和所有相关结构组成，包括 角膜、结膜和利姆布斯的表面和腺上皮，以及泪腺和 睑板腺眼表在视觉中起着中心作用，并且眼表疾病和病症 表面和角膜是视力问题的主要原因。开发、建立和维护 依赖于基因网络的精确控制，这些基因网络受到 间充质-上皮相互作用在细胞水平。重要的是，神经嵴（NC）衍生的细胞引起 角膜和眼睑间充质，对眼表的形成至关重要。的长期目标 我们的实验室是为了阐明调节眼的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FOXC 2失活突变导致常染色体显性遗传综合征 淋巴水肿-双列吸虫病，其特征是肢体和四肢淋巴引流受阻， 生长异常，额外的睫毛（双睫）。我们已经完成了初步的实验，表明（1） 在小鼠中，NC特异性Foxc 2突变导致角膜结膜化、异位角膜 新生血管形成、睑板腺发育缺陷和眼上皮细胞身份受损，以及 (2)这种复合物，即Foxc 2和一个密切相关基因Foxc 1的NC特异性突变， 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Pitx 2及其下游效应子Dkk 2， Wnt信号。因此，我们的中心假设是，Foxc 2在NC衍生的细胞中是角膜内皮细胞生长所必需的。 发育和眼上皮细胞身份的建立。在强大的初步数据指导下， 将通过追求两个具体目标来验证假设：1）确定控制 角膜发育; 2）确定Foxc 2参与角膜形成的机制， 上皮细胞身份总之，这项研究是有意义的，因为我们的发现将有助于 这对更好地理解眼表的形成和角膜的建立有重要意义。 上皮身份这将对患者护理产生重要的积极影响，因为 拟议中的研究可能会导致识别新的目标和治疗策略，以改善视力 受影响的患者。