A novel regulator of corneal wound healing and Pseudomonas aeruginosa keratitis

项目摘要 在我们最近发表的工作中，我们发现含有CUB结构域的蛋白1（CDCP 1）是CD 6的一种新的重要配体，CD 6是T细胞的标志物和关键调节因子，证明了CDCP 1在免疫调节中的惊人作用。CDCP 1最初被发现在某些实体瘤细胞上过表达，调节肿瘤细胞失巢凋亡抗性。然而，CDCP 1在眼睛中的分布及其在组织稳态中的潜在作用尚不清楚。在我们最新的（未发表的）工作中，使用CDCP 1敲除（KO）小鼠和CDCP 1敲除的人角膜上皮细胞，我们发现CDCP 1在所有眼细胞中高度选择性地表达在角膜上皮细胞上，并且CDCP 1对于增强角膜创伤愈合至关重要。在这个计划中，我们将使用我们开发的独特的试剂和模型，包括CDCP 1-KO小鼠，CD 6-KO小鼠，CDCP 1-KO人角膜上皮细胞和重组突变CDCP 1蛋白，我们将阐明CDCP 1促进角膜伤口愈合的内在和外在机制。我们还将测试新的CDCP 1靶向方法，作为加速角膜伤口愈合的新疗法。拟议的工作将建立CDCP 1在角膜伤口愈合中以前未知的作用，促进这种角膜病理状况的新的有效疗法的开发，并为CDCP 1和角膜稳态的研究开辟新的途径。

Project Summary In our recently published work, we discovered that CUB-Domain-Containing Protein 1 (CDCP1) is a new and important ligand of CD6, which is a marker and a critical regulator of T cells, demonstrating a surprising role of CDCP1 in immune regulation. CDCP1 was originally discovered to be overexpressed on certain solid tumor cells, regulating tumor-cell anoikis resistance. However, the distribution of CDCP1 in the eye and its potential role in tissue homeostasis was unknown. In our latest (unpublished) work, using CDCP1 knockout (KO) mice and CDCP1 knocked down human corneal epithelial cells, we discovered that CDCP1 is highly and selectively expressed on corneal epithelial cells among all ocular cells, and that CDCP1 is critical for enhancing corneal wounding healing. In this proposed project, using the unique reagents and models that we have developed, including CDCP1-KO mice, CD6-KO mice, CDCP1-KO human corneal epithelial cells and recombinant mutant CDCP1 proteins, we will elucidate both the intrinsic and extrinsic mechanisms by which CDCP1 enhances corneal wound healing. We will also test novel CDCP1-targeted approaches as new therapeutics for accelerating corneal wound healing. The proposed work would establish a previously unknown role of CDCP1 in corneal wound healing, facilitate the development of new and effective therapies for this corneal pathological condition, and open a new avenue for research on CDCP1 and corneal homeostasis.