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：
8304520
负责人：
Thewarach Laha
金额：
$ 10.07万
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304520
关键词：
Address Adolescent Adult Age Apoptosis Apoptotic Area Australia Bile Duct Epithelium Bile duct carcinoma Biliary Binding Biological Products Cambodia Cancer Etiology Cancerous Carcinogens Cell Line Cell Proliferation Cells Cessation of life China Cholangiocarcinoma Cholecystitis Cholelithiasis Chronic Clonorchis sinensis Country Cutaneous DNA Damage Development Diet Disease Duodenum Eastern Europe Ecology Environment Epidemiology Epithelium Etiology Exhibits Far East Fasciola hepatica Fibroblasts Fibrosis Fishes Fresh Water Growth Factor Hamsters Health education Hepatobiliary Hepatomegaly Homologous Gene Human In Vitro Incidence Infection Inflammation Instruction Intervention Korea Laos Link Liver Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mitosis Modeling Molecular Mus Neoplasm Metastasis New York Northern Europe Obstructive Jaundice Opisthorchiasis Opisthorchis Opisthorchis viverrini Parasites Pathogenesis Pathology Pharmaceutical Preparations Philippines Physiological Praziquantel Prevalence Primary carcinoma of the liver cells Principal Investigator Process Proliferating Property Proteins Public Health Punch Biopsy Recombinants Reporting Research Role Route Secretory Component Skin Snails Staging Stream Thailand Time Trematoda Vaccinated Vaccines Vietnam Woman Work Wound Healing bile duct biliary tract carcinogenesis carcinogenicity cholangiocyte disorder control egg foodborne granulin health organization in vivo men migration outcome forecast parasitism pathogen secretory protein thioredoxin peroxidase tumor tumorigenesis tumorigenic

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 originafing 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 mulfi-factorial, but one mechanism is the secrefion 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) secrefion 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 administrafion of the anthelminfic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will invesfigate 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 intervenfion can protect against liver fluke infecfion and CCA, and assessment of impact of repeated PZQ therapy in accelerafing tumorigenesis. RELEVANCE (See instructions): Despite treatment and health education campaigns, the prevalence of O. viverrini infection remains high in Northeast Thailand; more problemafically, infecfion with O. viverrini often leads to a deadly form of liver cancer. The work proposed here invesfigates - at the molecular level - how liver fluke infection causes this liver cancer, and could offer new strategies to control this disease.

该研究涉及由肝吸虫感染引起的胆管癌（CCA）、胆管癌、维韦里尼后睾丸。 CCA 是一种起源于胆汁上皮（胆管细胞）的原发性癌症管道。它潜伏期长、具有侵袭性、易转移且预后较差。其机制吸虫的慢性感染导致CCA可能是多因素的，但其中一种机制是分泌具有促有丝分裂和抗凋亡特性的寄生虫蛋白，这是癌前细胞的两个特征环境。我们对 O. viverrini 的排泄/分泌 (ES) 产物进行了表征，并确定了两种候选 ES 蛋白是这些过程的核心 - 我们发现人类的同源物分泌的生长因子、颗粒蛋白与胆管细胞结合并刺激成纤维细胞和 CCA 的增殖细胞系。我们还表明，分泌的硫氧还蛋白过氧化物酶可以阻止受损细胞的凋亡。胆管细胞。慢性后睾丸病进展为 CCA 遵循多因素途径。我们假设沿途的关键过程包括（1）寄生虫蛋白的分泌，其诱导胆道病理学并通过促进建立有利于癌症发展的环境细胞增殖和DNA损伤，加速伤口愈合并阻止细胞凋亡； (2) 重复使用驱虫药吡喹酮治疗 O. viverrini (Ov) 感染，会导致胆管炎症增加，从而加速肿瘤发生。该研究将调查通过评估 Ov-ES 的能力来评估这些现象：(1) 促进哺乳动物细胞的伤口修复； (2) 促进细胞侵袭和迁移； (3)干扰细胞凋亡。为了进一步解决致癌作用这些蛋白质，我们将用 Ov-ES 及其定义的成分给仓鼠接种疫苗，以确定这是否干预措施可以预防肝吸虫感染和 CCA，并评估重复 PZQ 的影响加速肿瘤发生的治疗。相关性（参见说明）：尽管开展了治疗和健康教育活动，O. viverrini 感染的流行率仍然很高泰国东北部；更严重的问题是，O. viverrini 感染通常会导致致命的肝脏疾病癌症。这里提出的工作在分子水平上研究了肝吸虫感染如何导致这种情况肝癌，并可能提供控制这种疾病的新策略。