A novel regulator of Pseudomonas aeruginosa keratitis

摘要 CD 6是T细胞的关键调节因子，其存在于包括γδ T细胞在内的所有T细胞上。在我们最近 在已发表的工作中，我们发现含CUB结构域的蛋白1（CDCP 1）是一种新的重要配体 在CD 6这一新发现证明了CDCP 1在免疫调节中的惊人作用。CDCP 1是 最初被发现是在某些实体瘤细胞上过表达的跨膜蛋白， 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眼内的潜在作用， 眼免疫和组织内稳态是未知的。在我们最新的（未发表的）工作中，我们使用了primary 人和小鼠角膜上皮细胞，以及CDCP 1和CD 6敲除（KO）小鼠，以证明 这是首次发现CDCP 1在正常角膜上皮细胞上高度选择性表达， 细胞，并且CDCP 1对于控制铜绿假单胞菌角膜感染至关重要，其潜在机制 整合地涉及表达CD 6的γδ T细胞。在这个项目中，我们将使用独特的试剂和模型 包括CDCP 1-KO小鼠、CD 6-KO小鼠、γδ T细胞缺陷小鼠、CDCP 1-KO人 角膜上皮细胞和重组CDCP 1蛋白，以阐明内在和外在机制 CDCP 1通过其控制角膜的细菌感染。我们还将测试新的CDCP 1靶向方法 作为管理铜绿假单胞菌角膜炎的新治疗策略。拟议的工作预计将建立 CDCP 1在铜绿假单胞菌角膜炎发病机制中的作用是以前未知的， 新的和有效的治疗这种痛苦和致盲的疾病，并开辟了一个新的途径，研究 CDCP 1在角膜免疫稳态中的作用

ABSTRACT CD6 is a critical regulator of T cells that is present on all T cells including γδ T cells. In our recently published work, we discovered that CUB-Domain-Containing Protein 1 (CDCP1) is a new and important ligand of CD6. This new discovery demonstrated a surprising role of CDCP1 in immune regulation. CDCP1 was originally discovered as an overexpressed transmembrane protein on certain solid tumor cells intrinsically regulating tumor-cell anoikis resistance. However, the distribution of CDCP1 in the eye and its potential role in ocular immunity and tissue homeostasis were unknown. In our latest (unpublished) work, we used primary human and mouse corneal epithelial cells, as well as CDCP1- and CD6-knockout (KO) mice, to demonstrate for the first time that CDCP1 is highly and selectively expressed on normal corneal epithelial cells among all ocular cells, and that CDCP1 is critical for controlling P. aeruginosa corneal infection, whose underlying mechanisms integrally involve CD6-expressing γδ T cells. In this proposed project, we will use unique reagents and models that we have developed, including CDCP1-KO mice, CD6-KO mice, γδ T cell-deficient mice, CDCP1-KO human corneal epithelial cells and recombinant CDCP1 proteins, to elucidate both intrinsic and extrinsic mechanisms by which CDCP1 controls bacterial infection of the cornea. We will also test novel CDCP1-targeted approaches as new therapeutic strategies for managing P. aeruginosa keratitis. The proposed work is expected to establish a previously unknown role of CDCP1 in the pathogenesis of P. aeruginosa keratitis, facilitate the development of new and effective therapies for this painful and blinding disease, and open a new avenue for research on CDCP1 in corneal immunohomeostasis.