Opisthorchis Viverrini ES Proteins and the Tumorgenic Environment

Opisthorchis Viverrini ES 蛋白和致瘤环境

基本信息

批准号：
8919230
负责人：
Thewarach Laha
金额：
$ 10.09万
依托单位：
KHON KAEN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8919230
关键词：
Address Anthelmintics Apoptosis Apoptotic Area Bile Duct Epithelium Bile duct carcinoma Binding Cancer Etiology Cancerous Carcinogens Cell Line Cell Proliferation Cells Cessation of life Cholangiocarcinoma Chronic Country Cutaneous DNA Damage Development Diet Ecology Environment Epithelium Exhibits Fasciola hepatica Fibroblasts Fishes Growth Factor Hamsters Health education Homologous Gene Human In Vitro Incidence Infection Inflammation International Agency for Research on Cancer Intervention Laos Link Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mitosis Modeling Molecular Mus Neoplasm Metastasis New York Opisthorchiasis Opisthorchis viverrini Parasites Pathogenesis Pathology Pharmaceutical Preparations Physiological Praziquantel Prevalence Process Proliferating Property Protein Secretion Proteins Public Health Punch Biopsy Recombinants Reporting Research Role Route Secretory Component Thailand Time Trematoda Vaccinated Work World Health Organization Wound Healing bile duct biliary tract carcinogenesis carcinogenicity cholangiocyte disorder control granulin in vivo migration outcome forecast parasitism pathogen secretory protein thioredoxin peroxidase tumor tumorigenesis tumorigenic uncooked vaccine trial

项目摘要

The research deals with cholangiocarcinoma (CCA), bile duct cancer, caused by infection with the liver fluke, Opisthorchis viverrini. CCA is a primary cancer originating in the epithelium (cholangiocytes) ofthe bile ducts. It has long latency, is invasive, metastasizes and has a dismal prognosis. The mechanisms by which chronic infection with the flukes results in CCA are likely multi-factorial, but one mechanism is the secretion of parasite proteins with mitogenic and anti-apoptotic properties, both features of a pre-cancerous cellular environment. We have characterised the excretory/secretory (ES) products of O. viverrini and identified two candidate ES proteins that are central to these processes - we showed that a homologue of the human secreted growth factor, granulin, binds to cholangiocytes and stimulates proliferation of fibroblasts and CCA cell lines. We also showed that secreted thioredoxin peroxidase blocks apoptosis of damaged cholangiocytes. Progression of chronic opisthorchiasis to CCA follows a multi-factorial route(s). We hypothesize that key processes along the route include (1) secretion of parasite proteins which induce pathology in the biliary tract and establish an environment conducive to cancer development by promoting cell proliferation and DNA damage, accelerating wound healing and blocking apoptosis; and (2) repeated administration of the anthelmintic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will investigate these phenomena by assessing the ability of Ov-ES to (1) facilitate wound repair in mammalian cells; (2) promote cell invasion and migration; (3) interfere with apoptosis. To further address the carcinogenic roles of these proteins, we will vaccinate hamsters with Ov-ES and its defined components to determine whether this intervention can protect against liver fluke infection and CCA, and assessment of impact of repeated PZQ therapy in accelerating tumorigenesis.

该研究涉及胆管癌（CCA），胆管癌，是由肝fl虫感染的Opisthorchis viverrini引起的。 CCA是起源于胆管上皮（胆管细胞）的原发性癌。它具有长期的潜伏期，具有侵入性，转移且预后令人沮丧。慢性感染在CCA中导致慢性感染的机制可能是多因素的，但是一种机制是具有有丝分裂和抗凋亡特性的寄生虫蛋白的分泌，这是癌前细胞环境的这两种特征。我们已经表征了O. viverrini的排泄/分泌物（ES）产物，并确定了两个对这些过程至关重要的候选ES蛋白质 - 我们表明，人类分泌生长因子（颗粒蛋白）的同源物与胆管细胞结合并刺激了成纤维细胞和CCA细胞系的增殖。我们还表明，分泌的硫氧还蛋白过氧化物酶阻断受损的胆管细胞的凋亡。慢性粘菌病到CCA的进展遵循了多因素途径。我们假设沿途途径的关键过程包括（1）寄生虫蛋白的分泌，这些寄生虫蛋白在胆道中诱导病理学，并通过促进细胞增殖和DNA损伤，加速伤口愈合并阻止凋亡来建立有利于癌症发展的环境；（2）重复施用驱虫药物的药物，用于治疗O. viverrini（OV）感染，导致胆管的炎症增加，从而导致肿瘤发生。该研究将通过评估OV-E（1）促进哺乳动物细胞伤口修复的能力来研究这些现象；（2）促进细胞侵袭和迁移；（3）干扰凋亡。为了进一步解决这些蛋白质的致癌作用，我们将用OV-ES及其定义的成分接种仓鼠，以确定该干预措施是否可以预防肝氟氟化物感染和CCA，并评估重复的PZQ治疗在加速肿瘤发生中的影响。