A novel regulator of Pseudomonas aeruginosa keratitis

铜绿假单胞菌角膜炎的新型调节剂

• 批准号: 10401830
• 负责人: FENG C LIN
• 金额: $ 54.86万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401830
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Address; Affinity; Anoikis; Anti-Bacterial Agents; Antibacterial Response; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Binding; CD14 Antigen; CD14 gene; CD6 antigen; Cell Proliferation; Cell Survival; Cell surface; Cells; Chemotactic Factors; Clinical; Contact Lenses; Cornea; Development; Disease; Economics; Environment; Epithelial Cells; Exhibits; Eye; Homeostasis; Human; Immunity; Infection; Inflammatory Response; Integral Membrane Protein; Interleukin-17; Invaded; Keratitis; Knock-out; Knockout Mice; Ligands; Mediating; Modeling; Mouse Strains; Mus; Neutrophil Infiltration; Non-Malignant; Pain; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phase; Physiological; Prevention strategy; Production; Prophylactic treatment; Proteins; Proto-Oncogene Proteins c-akt; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Publishing; Reagent; Recombinants; Reporting; Research; Resistance; Role; Serine Protease; Signal Transduction; Solid Neoplasm; Steroids; T cell response; T-Lymphocyte; Testing; Time; Tissues; Treatment Protocols; Tumor-infiltrating immune cells; United States; Variant; Vision; Visit; Work; antimicrobial; antimicrobial peptide; base; biophysical techniques; cell type; corneal epithelium; effective therapy; immunoregulation; microbial; mutant; neoplastic cell; neutrophil; non-oncogenic; novel; novel therapeutic intervention; novel therapeutics; overexpression; recombinant adenovirus; recruit; response; selective expression; side effect; social; targeted treatment; treatment strategy; unpublished works; γδ T cells

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.

摘要 CD6是T细胞的重要调节因子，存在于包括γδT细胞在内的所有T细胞上。在我们最近 在发表的工作中，我们发现Cub结构域包含蛋白1(CDCP1)是一种新的重要的配体 CD6。这一新发现展示了CDCP1在免疫调节中令人惊讶的作用。CDCP1是 最初在某些实体肿瘤细胞上被发现为一种本质上过度表达的跨膜蛋白 调节肿瘤细胞的失巢抵抗。然而，CDCP1在眼睛中的分布及其在眼部疾病中的潜在作用 眼球免疫和组织动态平衡尚不清楚。在我们最新的(未发布的)工作中，我们使用了主 人和小鼠角膜上皮细胞，以及CDCP1和CD6基因敲除(KO)小鼠，以展示 CDCP1首次在正常角膜上皮细胞高选择性表达 CDCP1是控制铜绿假单胞菌角膜感染的关键，其基本机制是 包括表达CD6的γδT细胞。在这个拟议的项目中，我们将使用独特的试剂和模型 包括CDCP1KO小鼠、CD6KO小鼠、γδT细胞缺陷小鼠、CDCP1KO人 角膜上皮细胞和重组CDCP1蛋白，以阐明内在和外在机制 CDCP1通过它控制角膜的细菌感染。我们还将测试以CDCP1为目标的新方法 作为治疗铜绿假单胞菌角膜炎的新策略。拟议的工作预计将建立 CDCP1在铜绿假单胞菌角膜炎发病机制中的作用 为这种痛苦和致盲的疾病提供新的有效治疗方法，并开辟了一条研究 CDCP1在角膜免疫稳态中的作用