EGFR-MEDIATED CORNEAL EPITHELIAL WOUND HEALING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 角膜上皮伤口愈合和稳态受EGFR活性调节。 这一过程由三种细胞变化介导：细胞迁移、增殖和分层。通过小分子抑制剂或阻断抗体抑制配体刺激的EGFR活化，导致所有三种细胞变化减少以及伤口愈合受损。 基于我们自己的发现和其他人的工作，我们假设角膜伤口愈合可以通过促进EGFR介导的信号来增强细胞迁移。为了验证这一假设，我们必须在分子和细胞水平上了解EGFR介导的信号传导。这些信息将用于靶向促进上皮细胞迁移的分子和机制，这最终可以加速受损区域的覆盖和受伤角膜的愈合。 在本建议的第一个目标中，我们将研究其他内源性EGFR配体，这些配体已被报道为更有效的角膜伤口愈合激活剂。我们假设这些配体促进EGFR与EGF不同的内吞运输路线（即回收而不是降解），这是它们增强伤口愈合的基础。 在第二个目标中，我们将破坏EGFR内吞运输的离散阶段沿着内吞途径和评估的EGFR磷酸化，效应信号和细胞生理的幅度和持续时间。 这些发现将表明激活受体在离散内吞位置的富集是否将特异性地促进与角膜伤口愈合相关的分子和细胞事件。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Corneal epithelial wound healing and homeostasis is regulated by EGFR activity. This process is mediated by three cellular changes: cell migration, proliferation, and stratification. Inhibition of ligand-stimulated EGFR activation, either through small molecule inhibitors or blocking antibodies, results in a decrease in all three cellular changes as well as impaired wound healing. Based on our own findings and the work of others, we hypothesize that corneal wound healing can be enhanced by promoting EGFR-mediated signals that enhance cell migration. To test this hypothesis, we must understand EGFR-mediated signaling on the molecular and cellular level. This information will be used to target molecules and mechanisms that promote epithelial cell migration, which can ultimately accelerate coverage of the damaged area and healing of the wounded cornea. In the first aim of this proposal, we will study other endogenous EGFR ligands that have been reported to be more potent activators of corneal wound healing. We hypothesize that these ligands promote different endocytic trafficking itineraries of the EGFR than EGF (i.e. recycling rather than degradation) and this is the basis of their enhance wound healing. In the second aim, we will disrupt EGFR endocytic trafficking at discrete stages along the endocytic pathway and assess the magnitude and duration of the EGFR phosphorylation, effector signaling, and cell physiology. These findings will indicate whether enrichment of the activated receptor at discrete endocytic location will specifically promote the molecular and cellular events associated with corneal wound healing.