Intestinal inflammation and genotoxicity of the colonic-adherent microbiota

描述(由申请人提供)：炎症性肠病(IBD)患者患炎症相关结直肠癌(I-CRC)的风险增加，这是通过炎症环境对宿主和微生物区系的影响而调节的。然而，目前尚不清楚炎症如何随着时间的推移影响结肠黏附微生物群的组成，炎症相关微生物的功能，以及这些能力如何增强炎症和I-CRC。我的研究兴趣集中在了解IBD微环境如何改变微生物区系的促炎和致癌能力，目标是将这些微生物作为一种治疗策略，以减轻炎症和降低I-CRC的风险。我的直接目标是建立一个独立的基础和转化性研究领域，与我的导师截然不同，与临床相关，并可能吸引持续的资金。我将通过以下培训目标实现这些目标：(I)发展必要的技能和专业知识，以机械地评估 这些研究包括：(1)研究微生物区系及其对肠道炎症和I-CRC的影响之间的关系；(2)产生创新数据，在高质量的同行评议期刊上发表，并获得独立资助。实现这些目标将使我能够实现我的长期职业目标，领导一个多学科的科学家团队，并作为一名独立资助的学术研究人员成功地从事创新的消化系统疾病研究。目前这项提案的科学目标是定义炎症诱导的粘膜粘附性微生物区系的变化，并证明炎症相关的基因毒性肠杆菌科对癌症的促进作用。在IBD患者和小鼠模型中观察到粘膜粘附性细菌增加，特别是肠杆菌科细菌。这使这些细菌处于与宿主上皮细胞相互作用并发挥促炎和促癌活性的理想位置。我们假设炎症支持基因毒性肠杆菌科细菌在结肠粘膜的扩张，这通过增加DNA损伤来增加I-CRC。我们将在两个具体目标上检验这一假设。在目标1中，我们将定义炎症对白细胞介素10缺陷(IL10-/-)小鼠结肠黏附微生物群组成的影响。在目标2中，我们将利用现代测序技术和GnotoBiotic I-CRC小鼠模型分离、表征和测试结肠粘附性、炎症相关、遗传毒性肠杆菌科细菌的促癌活性。北卡罗来纳大学教堂山的环境中有两个对这些研究至关重要的独特核心：高通量测序核心和NIH资助的国家灵生啮齿动物资源中心。展示炎症相关基因毒素细菌的癌症促进作用，并识别促进I-CRC的特定微生物和微生物途径，将揭示可能预测IBD患者I-CRC风险增加的新靶点，并有助于针对新的选择性治疗。

DESCRIPTION (provided by applicant): Patients with inflammatory bowel diseases (IBD) experience an increased risk of inflammation-associated colorectal cancer (I-CRC), mediated through the effects of the inflammatory environment on both the host and the microbiota. However, it remains unclear how inflammation impacts the composition of the colonic-adherent microbiota over time, the functional capabilities of inflammation-associated microbes, and how these capabilities augment inflammation and I-CRC. My research interests focus upon understanding how the IBD microenvironment alters the pro-inflammatory and pro-carcinogenic capabilities of the microbiota with the goal of targeting these microbes as a therapeutic strategy to lessen inflammation and reduce the risk of I-CRC. My immediate goals are to establish an independent area of basic and translational research that is distinct from my mentors, clinically relevant, and likely to attract continuous funding. I will accomplish these goals with the followin training objectives: (I) develop the necessary skills and expertise to mechanistically evaluate the relationship between the microbiota and its effects on intestinal inflammation and I-CRC, and (II) generate innovative data to publish in high quality peer-reviewed journals and obtain independent funding. Attaining these goals will allow me to reach my long-term career goal, to lead a team of multidisciplinary scientists and succeed as an independently funded academic investigator pursuing innovative digestive diseases research. The scientific objective of the current proposal is to define inflammation-induced alterations to the mucosally- adherent microbiota and demonstrate the cancer-promoting impact of inflammation-associated genotoxic Enterobacteriaceae. Increased mucosally-adherent bacteria, particularly Enterobacteriaceae, are observed in IBD patients and mouse models. This positions these bacteria at an ideal location in which to interact with host epithelial cells and exert pro-inflammatory and pro-carcinogenic activities. We hypothesize that inflammation supports the expansion of genotoxic Enterobacteriaceae at the colonic mucosa and this augments I-CRC through increased DNA damage. We will test this hypothesis in two Specific Aims. In Aim 1, we will define the impact of inflammation on the composition of the colonic-adherent microbiota over time in Interleukin-10- deficient (Il10-/-) mice. In Aim 2, we will isolate, characterize and test the cancer-promoting activity of colonic- adherent, inflammation-associated, genotoxic Enterobacteriaceae using modern sequencing technology and gnotobiotic I-CRC mouse models. The environment at UNC Chapel Hill houses two unique cores that are essential for these studies: the High Throughput Sequencing Core and the NIH-funded National Gnotobiotic Rodent Resource Center. Demonstrating a cancer-promoting effect of inflammation-associated genotoxic bacteria and identifying specific microbes and microbial pathways that promote I-CRC will reveal novel targets that may be predictive of an elevated risk for I-CRC in IBD patients and help target novel selective therapies.