Notch Signaling in the Corneal Epithelium

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。目前，调节角膜上皮细胞分化和更新的途径在很大程度上是未知的。了解角膜上皮细胞再生的精确调控途径，对于开发有效的治疗多种角膜创伤愈合疾病的方法至关重要。Notch信号通路是决定细胞命运的重要途径，近年来被认为与角膜上皮细胞的生长和分化有关。这项应用的长期目标有两个方面。首先，通过确定Notch信号在调节角膜上皮生长和分化中的作用，为眼表疾病患者的新的和创新的治疗方法的开发做出贡献。第二，进一步发展申请人作为临床科学家的职业生涯，促进他向独立研究人员的过渡。为了实现这一应用的研究目标，将追求以下三个具体目标：(1)检测Notch受体及其配体在角膜上皮细胞增殖和分化过程中的表达。(2)研究Notch的激活和抑制对人角膜上皮细胞生长和分化的影响。(3)测定Notch对小鼠角膜上皮细胞的激活和抑制作用。除了追求这些具体目标外，申请者还将遵循精心设计的职业发展计划，包括在经验丰富的导师的直接监督下进行教学和实践培训。总体而言，这些研究将提高我们对眼睛表面是如何再生的理解。这些结果将导致开发新的治疗方法，用于治疗涉及眼表的致残视觉疾病患者。

DESCRIPTION (provided by applicant): The corneal epithelium is one of the most sensitive and critical structures of the eye. Currently, the pathways that regulate the differentiation and renewal of the corneal epithelial cells are largely unknown. Understanding the precise regulatory pathways governing corneal epithelial regeneration is critical for the development of effective treatments for many corneal wound healing disorders. Notch signaling, which is an important pathway in cell-fate determination, has recently been implicated in corneal epithelial growth and differentiation. The long-term objective of this application is two fold. First, is to contribute to the development of novel and innovative treatments for patients with ocular surface disease by defining the role of Notch signaling in the regulation of corneal epithelial growth and differentiation. Second, is to further develop the career of the applicant as a clinician-scientist and facilitate his transition to becoming an independent investigator. To accomplish the research objectives of this application, the following three specific aims will be pursued: (1) Determine the expression of Notch receptors and ligands in the corneal epithelial cells during proliferation and differentiation. (2) Characterize the effects of induced Notch activation and inhibition on the growth and differentiation of the human corneal epithelial cells. (3) Determine the in vivo effects of Notch activation and inhibition in the murine corneal epithelium. In addition to pursuing these specific aims, the applicant will follow a carefully designed career development plan involving didactic and hands-on training under the direct supervision of experienced mentors. Overall, these studies will improve our understanding of how the surface of the eye is regenerated. These results will lead to the development of new treatments for patients with disabling visual conditions involving the surface of the eye.