A Zebrafish Model to Study the Role of the Microbiota in the Etiology of Intestin

研究微生物群在肠病因学中的作用的斑马鱼模型

基本信息

批准号：
8997473
负责人：
Karen J Guillemin
金额：
$ 28.99万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997473
关键词：
Aeromonas Alleles Animal Model Anti-Inflammatory Agents Anti-inflammatory Bacteria Cancer Etiology Cell Proliferation Chromosomal Instability Chronic Communities Complex DNA Damage DNA Repair Development Diagnosis Disease Disease Outbreaks Dissection Environment Epithelial Epithelial Cell Proliferation Etiology Fishes Gastritis Gastrointestinal tract structure Genes Genetic Genetic Programming Gnotobiotic Health Helicobacter Infections Helicobacter pylori Homeostasis Host Defense Housing Human Human Genetics Hyperplasia Individual Inflammation Integration Host Factors Intestinal Cancer Intestines Lead Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Microbe Modeling Mutation Neoplasms Normal tissue morphology Oncogenes Oncogenic Organ Pathology Pathway interactions Process Property Proteins Research Role Signal Pathway Signal Transduction Signaling Molecule Stomach TP53 gene Testing Tissues Transgenic Organisms Tumor Suppressor Genes Vibrio cholerae Zebrafish beta catenin carcinogenesis data integration gut microbiota innovation insight intestinal homeostasis malignant stomach neoplasm member microbial microbial community microbial host microbiome microbiota microorganism novel strategies nutrition pathogen prevent programs transmission process

项目摘要

DESCRIPTION (provided by applicant): The human gastrointestinal tract houses large and complex communities of microorganisms that are important for normal health, but can also contribute to diseases such as gastrointestinal cancer. In this proposal we will use a zebrafish model to investigate how factors produced by gut microbes interact with host genetic factors to drive the progression of intestinal cancer. We will make use of zebrafish lines that are predisposed to intestinal cancer due to over-activation of the Wnt signaling pathway, chronic inflammation, or loss of DNA repair mechanisms, all of which are commonly associated with gastrointestinal cancers in humans. In our first aim we will characterize a number of secreted proteins, produced by both human and zebrafish-associated bacteria, that modulate host programs associated with gastrointestinal cancer development, including epithelial cell proliferation and inflammation. We will determine whether the pro-proliferative proteins interacts synergistically with cancer-prone genetic backgrounds to disrupt normal programs of intestinal epithelial renewal and cause hyperplasia, and furthermore whether the anti-inflammatory proteins confer protection against hyperplasia. In our second aim we will characterize a transgenic zebrafish line that expresses the bacterial oncogene, CagA, from the stomach cancer-associated pathogen Helicobacter pylori. We will determine the host genetic programs that are activated during the progression of these transgenic fish to hyperplasia and cancer, and we will test which of these pathways are required for CagA's carcinogenic properties. We will also test whether CagA expression alters the intestinal microbial community in ways that promote intestinal pathology. In our third aim we will investigate the microbial etiology behind an outbreak of spontaneous intestinal cancers in our zebrafish facility, which we have shown to be transmissible. We will use the experimental framework of transmissible disease to identify microbes associated with intestinal pathology. We will employ our cancer- prone zebrafish lines to characterize the carcinogenic potential of disease-associated microbial communities and of individual candidate microbes. This research will provide new insight into the mechanisms by with intestinal microbes contribute to cancer development and will ultimately lead to new approaches to diagnose, treat and prevent gastrointestinal cancers in humans.

描述（由申请人提供）：人类胃肠道具有大型且复杂的微生物群落，这些微生物对正常健康很重要，但也可能导致诸如胃肠癌之类的疾病。在此提案中，我们将使用斑马鱼模型来研究肠道微生物产生的因素如何与宿主遗传因子相互作用以驱动肠癌的进展。由于Wnt信号通路，慢性炎症或DNA修复机制的丧失，我们将利用斑马鱼线易于肠道癌，这些斑马鱼通常与人类的胃肠道癌相关。在我们的第一个目的中，我们将表征许多由人和斑马鱼相关细菌产生的分泌蛋白，这些蛋白质调节与胃肠道癌发展相关的宿主程序，包括上皮细胞增殖和炎症。我们将确定促增生性蛋白是否与容易发生癌症的遗传背景协同相互作用，以破坏肠上皮更新的正常程序并引起增生，还可以赋予抗炎蛋白赋予对增生的保护。在我们的第二个目标中，我们将表征从胃癌相关的病原体幽门螺杆菌中表达细菌癌基因CAGA的转基因斑马鱼线。我们将确定这些转基因鱼类对增生和癌症的进展过程中被激活的宿主遗传程序，我们将测试CAGA的致癌特性所需的这些途径中的哪些途径。我们还将测试CAGA表达是否以促进肠道病理的方式改变肠道微生物群落。在我们的第三个目标中，我们将研究一个背后的微生物病因斑马鱼设施中自发性肠癌的爆发，我们已证明是可以传播的。我们将使用可传染性疾病的实验框架来识别与肠道病理相关的微生物。我们将利用癌症斑马鱼线来表征与疾病相关的微生物群落和个别候选微生物的致癌潜力。这项研究将通过肠道微生物有助于癌症发展的机制提供新的见解，并最终导致新的诊断，治疗和预防人类胃肠道癌的方法。