Molecular mechanism of corneal epithelial stratification and innervation

角膜上皮分层和神经支配的分子机制

• 批准号: 10855640
• 负责人: CHIA-YANG LIU
• 金额: $ 45.15万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10855640
• 关键词: Molecular; mechanism; corneal; epithelial; stratification

PROJECT SUMMARY/ABSTRACT Corneal epithelium (CE) is composed of a single layer of basal cells and 4-5 cell layers of non- keratinized, stratified squamous epithelial cells to form an effective barrier against fluid loss and pathogen. CE is mainly innervated by trigeminal sensory afferents with extremely high density, which offers enormous sensitivity to the environmental insults for protecting otherwise deeper ocular tissues from damage by modulating the blink response and stimulating lacrimation. Any disruption of CE stratification and innervation can have deleterious effects on the integrity of the cornea and lead to neurotrophic keratopathy and corneal blindness. Little is known regarding the molecular and cellular mechanisms by which CE stratification and innervation is achieved during corneal morphogenesis and continuously sustained in the adulthood. In this proposal, we attempt to explore Shp2-mediated Ras–mitogen-activated protein kinase (Ras-MAPK) pathway which is extremely important for wide variety of cellular activities and behaviors, but it has not been studied in the CE stratification and innervation. We hypothesize that Shp2-mediated MAPK signaling controls CE stratification and innervation via regulating ∆Np63 expression. Three aims are proposed: Aim 1 is to elucidate the role of Shp2→Ras→Mek→∆Np63→E-cadherin signaling pathway in corneal epithelial stratification during and following development. Aim 2 is to elucidate the role of Shp2→Ras→Mek→∆Np63→NGF signaling axis of the CE on the CNV1 innervations during and following development. Aim 3 is to rescue otherwise impaired CE stratification and innervation by overexpression of ∆Np63α in Shp2cko mice. Completion of proposed objectives will delineate mechanistic event related to the Shp2-mediated Ras-MAPK pathway to fine-tune ∆Np63, which in turn regulate E-cadherin and NGF, to faciliate stratification and innervation of CE during development and in the maintenance of corneal homeostasis. This knowledge has great potential to lead to the discovery of pathway-based molecular target to treat corneal diseases such as neurotrophic keratopathy.

项目总结/文摘