EGFR-MEDIATED CORNEAL EPITHELIAL WOUND HEALING

EGFR 介导的角膜上皮伤口愈合

• 批准号: 8360408
• 负责人: BRIAN P. CERESA
• 金额: $ 9.71万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360408
• 关键词: Blocking Antibodies; Cell membrane; Cells; Clathrin-Coated Vesicles; Complex; EGF gene; Early Endosome; Epidermal Growth Factor Receptor; Epithelial Cells; Funding; Future; Goals; Grant; Homeostasis; Impaired wound healing; Ligands; Lysosomes; Mediating; Mentors; National Center for Research Resources; Oklahoma; Pathway interactions; Physiological; Principal Investigator; Receptor Activation; Receptor Signaling; Research; Research Infrastructure; Resources; Signal Transduction; Source; Staging; Stratification; Therapeutic; Therapeutic Uses; Transforming Growth Factor alpha; United States National Institutes of Health; Vision research; Wound Healing; cell motility; corneal epithelium; cost; desensitization; inhibitor/antagonist; late endosome; receptor; receptor recycling; small molecule; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Corneal epithelial wound healing and homeostasis is regulated by Epidermal Growth Factor Receptor (EGFR) activity. Stimulation of the EGFR in corneal epithelial cells induces the three cellular changes associated with corneal epithelial wound healing: 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. Despite evidence that the EGFR is necessary and sufficient for corneal epithelial homeostasis and wound healing, EGF has limited therapeutic utility. We hypothesize that desensitization of the EGFR limits the therapeutic use of EGF ligands. Desensitization occurs through internalization of the ligand:receptor complex via clathrin-coated vesicles into the cell. This complex traffics through the endocytic pathway through early and late endosomes and culminates with the lysosomal degradation of the complex. We have identified transforming growth factor-alpha (TGF-alpha) as a ligand that alters the itinerary of endocytic trafficking of the ligand:receptor complex. Treatment with TGF-alpha promotes internalization of the ligand:receptor complex, but rather than targeting it to the lysosome, promotes receptor recycling to the plasma membrane. As a result, the EGFR can signal for longer. The physiological consequence of enhanced signaling is an increase in corneal epithelial cell migration. Since it is not clear if the increase in cell migration is due to the duration of EGFR signaling or the spatial placement of signaling, future studies will disrupt endocytic trafficking at discrete endocytic stages with the goal of making this distinction.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 角膜上皮伤口愈合和体内平衡受表皮生长因子受体（EGFR）活性调节。 刺激角膜上皮细胞中的 EGFR 会诱导与角膜上皮伤口愈合相关的三种细胞变化：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 激活，会导致所有三种细胞变化减少以及伤口愈合受损。尽管有证据表明 EGFR 对于角膜上皮稳态和伤口愈合是必要且充分的，但 EGF 的治疗效用有限。 我们假设 EGFR 的脱敏限制了 EGF 配体的治疗用途。 脱敏是通过配体：受体复合物通过网格蛋白包被的囊泡内化到细胞中而发生的。 该复合物通过早期和晚期内体的内吞途径运输，并以复合物的溶酶体降解达到顶峰。 我们已经确定转化生长因子-α（TGF-α）作为配体，可以改变配体：受体复合物的内吞运输行程。 TGF-α治疗促进配体：受体复合物的内化，但不是将其靶向溶酶体，而是促进受体再循环至质膜。 因此，EGFR 的信号传导时间可以更长。 信号传导增强的生理后果是角膜上皮细胞迁移的增加。 由于尚不清楚细胞迁移的增加是否是由于 EGFR 信号传导的持续时间或信号传导的空间位置所致，因此未来的研究将破坏离散内吞阶段的内吞运输，以期做出这种区分。