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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：
10618396
负责人：
FENG C LIN
金额：
$ 56.56万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618396
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 IL17 gene Immunity Infection Inflammatory Response Integral Membrane Protein 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 Proliferating Proteins Proto-Oncogene Proteins c-akt Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Reaction Reagent Recombinants Reporting Research Resistance Role Serine Protease Signal Transduction Solid Neoplasm Steroids T cell infiltration T cell response T-Lymphocyte Testing Time Tissues Treatment Protocols United States Variant Vision Visit Work antimicrobial antimicrobial peptide biophysical techniques cell type corneal epithelium effective therapy immunoregulation microbial mutant neoplastic cell neutrophil non-oncogenic novel novel therapeutic intervention novel therapeutics overexpression prophylactic recombinant adenovirus recruit response selective expression side effect social targeted treatment treatment strategy 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 In our latest (unpublished) work, we used primary human and mouse corneal epithelial cells, as well as CDCP1- and CD6-knockout (KO) mice, to demonstrate for the first time that CDCP1 is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.

摘要