Role of CDCP1 in the pathogenesis of autoimmune uveitis

CDCP1在自身免疫性葡萄膜炎发病机制中的作用

基本信息

批准号：
10655755
负责人：
FENG C LIN
金额：
$ 50.4万
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：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655755
关键词：
Activated-Leukocyte Cell Adhesion Molecule Active Immunization Adoptive Transfer Arrestins Attenuated Autoimmune Diseases Biological Assay Blindness Blocking Antibodies Blood-Retinal Barrier CD6 antigen Cell surface Cytoskeleton Data Development Disease Endothelium Epithelium Event Extracellular Domain Flow Cytometry Genetic Human Impairment In Vitro Infiltration Interleukin-6 Knock-out Knockout Mice Knowledge Ligands Mediating Monoclonal Antibodies Mus Myosin ATPase Pathogenicity Pathologic Penetration Permeability Phosphorylation Pre-Clinical Model Process Production Proteins Proteomics Reagent Reporting Research Retina Role Signal Transduction Stress Fibers Structure of retinal pigment epithelium Surface Surface Plasmon Resonance T cell infiltration T cell regulation T cell response T-Cell Activation T-Lymphocyte TFRC gene Testing Therapeutic Uses Therapeutic antibodies Tight Junctions Treatment Efficacy Uveitis Work autoimmune pathogenesis autoimmune uveitis cell motility conditional knockout cytokine efficacy evaluation extracellular immunogenicity immunoregulation in vivo inhibiting antibody insight knock-down migration mutant nanobodies new therapeutic target next generation novel novel therapeutic intervention protein protein interaction receptor selective expression targeted treatment therapeutic target

项目摘要

ABSTRACT Autoimmune uveitis is a major cause of blindness for which no cure and limited treatment options are available. We found that CUB domain-containing protein 1 (CDCP1) knockout (KO) mice are protected from experimental autoimmune uveitis (EAU) induced by adoptive transfer of pre-activated uveitogenic T cells, suggesting that CDCP1 facilitates pathogenic T cell infiltration through the blood–retina barrier (BRB) to induce EAU. In pilot mechanistic studies, we discovered that CDCP1 is selectively expressed on retinal pigmented epithelial cells (RPEs) in the retina and identified CD71, an established T cell activation marker, as a new ligand of CDCP1 in addition to CD6, another T cell marker. Stimulation with CD6 or CD71 induced CDCP1-mediated RPE cytoskeletal remodeling, a process known to impair epithelial barrier functions, and increased RPE production of IL-6, a pathogenic cytokine known to disrupt the endothelial barrier integrity. These intriguing data provide strong evidence in support of CDCP1 as a novel immunoregulator that interacts with CD6 and CD71 on T cells to facilitate pathogenic T cell infiltration through the BRB to induce EAU. Further, our data suggest that CDCP1 could be targeted for treating autoimmune uveitis. In this proposed study, we aim to use the unique reagents that we have developed or obtained in our preliminary studies to elucidate the detailed mechanisms by which CDCP1 regulates both the outer and inner BRB to facilitate T cell infiltration into the retina, and to determine the potential of CDCP1-targeted therapeutics using various conditional KO mice and our already developed anti-CDCP1 monoclonal antibodies and nanobodies. The proposed work should provide novel insights into our understanding of the pathogenesis of autoimmune uveitis and open new avenues of research in which CDCP1 is explored as a key immunoregulator and new therapeutic target for this blinding disease.

抽象的自身免疫性葡萄膜炎是导致失明的主要原因，目前尚无治愈方法且治疗选择有限我们发现含有 CUB 结构域的蛋白 1 (CDCP1) 敲除 (KO) 小鼠受到保护。通过过继转移预激活的葡萄膜致性 T 细胞诱导实验性自身免疫性葡萄膜炎 (EAU)，表明CDCP1促进致病性T细胞通过血视网膜屏障（BRB）渗透，从而诱导 EAU。在初步机制研究中，我们发现CDCP1选择性地在视网膜色素上表达。视网膜上皮细胞 (RPE) 并鉴定出 CD71（一种已确定的 T 细胞激活标记物）作为新配体 CDCP1 和 CD6（另一种 T 细胞标记物）的刺激可诱导 CDCP1 介导。 RPE 细胞骨架重塑，这是一种已知会损害上皮屏障功能并增加 RPE 的过程 IL-6 的产生，这是一种已知会破坏内皮屏障完整性的致病细胞因子。提供强有力的证据支持CDCP1作为一种新型免疫调节剂，与CD6和CD71相互作用 T 细胞促进致病性 T 细胞通过 BRB 渗透以诱导 EAU。此外，我们的数据表明： CDCP1 可以作为治疗自身免疫性葡萄膜炎的目标。在这项拟议的研究中，我们的目标是使用独特的药物。我们在初步研究中开发或获得的试剂，以阐明详细的机制其中CDCP1调节外部和内部BRB以促进T细胞浸润到视网膜，并使用各种条件 KO 小鼠确定 CDCP1 靶向治疗的潜力，并且我们已经开发的抗CDCP1单克隆抗体和纳米抗体应提供新颖的工作。深入了解自身免疫性葡萄膜炎的发病机制并开辟新的研究途径其中CDCP1被探索作为这种致盲疾病的关键免疫调节剂和新的治疗靶点。