Intestinal inflammation and genotoxicity of the colonic-adherent microbiota

描述（由申请人提供）：炎症性肠病（IBD）患者发生炎症相关结直肠癌（I-CRC）的风险增加，这是通过炎症环境对宿主和微生物群的影响介导的。然而，目前尚不清楚炎症如何随时间影响结肠粘附微生物群的组成，炎症相关微生物的功能能力，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群的促炎和促癌能力，目标是将这些微生物作为减轻炎症和降低I-CRC风险的治疗策略。我的近期目标是建立一个独立的基础和转化研究领域，与我的导师不同，与临床相关，并有可能吸引持续的资金。我将通过以下培训目标来实现这些目标：(1)培养必要的技能和专业知识来机械地评估

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.