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

• 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
• 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

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）：人类胃肠道容纳着庞大而复杂的微生物群落，它们对正常健康很重要，但也可能导致胃肠道癌症等疾病。在这项提议中，我们将使用斑马鱼模型来研究肠道微生物产生的因子如何与宿主遗传因子相互作用以驱动肠癌的进展。我们将利用由于Wnt信号通路过度激活、慢性炎症或DNA修复机制缺失而易患肠癌的斑马鱼系，所有这些都通常与人类胃肠道癌症相关。在我们的第一个目标中，我们将描述由人类和斑马鱼相关细菌产生的一些分泌蛋白，这些蛋白调节与胃肠道癌症发展相关的宿主程序，包括上皮细胞增殖和炎症。我们将确定促增殖蛋白是否与易患癌症的遗传背景协同作用，从而破坏肠上皮的正常更新程序并导致增生，此外，抗炎蛋白是否赋予防止增生的保护作用。在我们的第二个目标中，我们将表征一种转基因斑马鱼系，该斑马鱼系表达来自胃癌相关病原体幽门螺杆菌的细菌致癌基因CagA。我们将确定在这些转基因鱼向增生和癌症发展过程中被激活的宿主遗传程序，我们将测试哪些途径是CagA致癌特性所必需的。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，我们将调查背后的微生物病因