A novel regulator of Pseudomonas aeruginosa keratitis

铜绿假单胞菌角膜炎的新型调节剂

基本信息

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
项目类别：
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recombinant adenovirus recruit response selective expression side effect social targeted treatment treatment strategy unpublished works γδ T cells

项目摘要

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 In our latest (unpublished) work, we used primary human and mouse corneal epithelial cells, as well as CDCP1- and CD6-knockout (KO) mice, to demonstrate for the first time that CDCP1 is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.

抽象的 CD6 是 T 细胞的关键调节因子，存在于所有 T 细胞上，包括 γδ T 细胞。发表的工作中，我们发现 CUB 结构域蛋白 1 (CDCP1) 是一种新的重要配体这一新发现证明了 CDCP1 在免疫调节中的惊人作用。最初发现为某些实体瘤细胞本质上过度表达的跨膜蛋白然而，CDCP1 在眼中的分布及其潜在作用。在我们最新的（未发表的）工作中，我们使用了初级的眼免疫和组织稳态。人类和小鼠角膜上皮细胞，以及 CDCP1 和 CD6 敲除 (KO) 小鼠，以证明首次在所有眼科疾病中CDCP1在正常角膜上皮细胞上高选择性表达 CDCP1 对于控制铜绿假单胞菌角膜感染至关重要，其潜在机制在这个拟议的项目中，我们将使用独特的试剂和模型。我们开发的包括CDCP1-KO小鼠、CD6-KO小鼠、γδT细胞缺陷小鼠、CDCP1-KO人类角膜上皮细胞和重组CDCP1蛋白，以阐明内在和外在机制通过CDCP1控制角膜的细菌感染，我们还将测试新的CDCP1靶向方法。作为治疗铜绿假单胞菌角膜炎的新治疗策略，拟议的工作有望建立。 CDCP1 在铜绿假单胞菌角膜炎的发病机制中以前未知的作用，促进了发展为这种痛苦且致盲的疾病提供新的有效疗法，并为研究开辟一条新途径 CDCP1 在角膜免疫稳态中的作用。