Mechanisms of Corneal Epithelial Disease and Repair

 描述(申请人提供)：角膜上皮是眼睛最敏感和最关键的结构之一。它几乎影响到眼表的每一种疾病，从角膜擦伤和干眼到严重的角膜融化和感染。目前，能够特异性增强角膜上皮功能的治疗方法非常有限。在……里面 特别是，对于角膜上皮屏障受损的患者，没有促进上皮修复的药物方法。这项研究的长期目标是通过确定上皮屏障疾病和修复的机制，为视力残疾眼表疾病患者开发新的和创新的治疗方法。我们的初步研究提供了强有力的证据，证明Notch1在调节角膜上皮屏障修复中起关键作用，因此Notch1-/-小鼠为研究角膜上皮屏障疾病提供了一个独特的模型。为了实现这一应用的研究目标，将追求以下两个特定目标：(1)以Notch1-/-小鼠为模型，表征上皮屏障功能和细胞-细胞黏附缺陷；(2)以Notch1-/-小鼠为模型，阐明在上皮损伤/修复过程中激活的炎症信号通路，并确定它们在炎症和化生发展中的作用。这些结果将为视力残疾眼表疾病患者的治疗方法的开发提供关键信息。我们将确定一些候选途径和药物，用于临床增强角膜上皮功能和抑制角膜炎症。

 DESCRIPTION (provided by applicant): The corneal epithelium is one of the most sensitive and critical structures of the eye. It is affected in nearly every disease of the ocular surface, ranging from corneal abrasions and dry eyes to severe corneal melts and infections. Currently, there are very limited treatments that can specifically enhance the corneal epithelial function. In particular, there are no pharmacologic approaches to promote epithelial repair in patients with a compromised corneal epithelial barrier. The long term objective of this research application is to contribute to the development of novel and innovative treatments for patients with visually disabling ocular surface diseases by defining the mechanisms of epithelial barrier disease and repair. Our preliminary studies provide strong evidence that Notch1 plays a key role in regulating the corneal epithelial barrier repair and thus Notch1-/- mice provide a unique model for studying corneal epithelial barrier disease. To accomplish the research objectives of this application, the following two specific aims will be pursued: (1) Characterize the epithelial barrir function and the cell-cell adhesion defect using mice with conditional loss of Notch1 as a model, (2) Elucidate the inflammatory signaling pathways that are activated during epithelial injury/repair and determine their role in the development of inflammation and metaplasia using Notch1-/- mice as a model. These results will provide critical information for the development of therapies for patients with visually disabling ocular surface disorders. We will identify a number of candidate pathways and drugs for clinically enhancing the function of the corneal epithelium and suppressing corneal inflammation.