Role of Bacteria in Colitis-Associated Colon Cancer

摘要： 在上一个资金周期中，我们证明了特定的微生物活动对 结直肠癌的发生，例如在B2的某些大肠杆菌中存在致病的PKS基因岛 负责合成次生代谢物Colibactin(Arthur，J.C.等人)。(2012)，《科学》 338(6103)，120-123)。此外，我们最近观察到硫化氢的存在与 儿童人群中(H_2S)产生菌(HSPB)与新发克罗恩病(CD)的严重性 (Mottawea，W.，等人，2016。NAT Commun 7，1-14。)。我们的长期目标是确定细菌如何寄主 相互作用影响结肠炎相关性结直肠癌的发展。当前竞技体育的目标 更新是为了确定宿主和环境因素如何调节细菌的致癌潜力。 这个项目的中心假设是宿主衍生的信号调节细菌产生的代谢物 来影响癌症的发生。提出这项研究的理由是，一旦我们了解了相互作用 在细菌和宿主之间，有可能针对特定的活动，从而发展结肠炎- 关联的CRC。我们计划测试我们的中心假设，并使用 遵循特定的目标。 目的1.明确细菌诱导的Il10-/-；Apcmin/+小鼠结直肠癌所必需的炎症条件。 目的2.建立细菌诱导的Il10-/-；Apcmin/+小鼠结直肠癌的时间机制。 目的3.确定特定细胞类型改变后的微生物反应和结直肠癌的发展 MYD88信号在IL10-/-小鼠中的表达。 这些结果不仅可能为结直肠癌的研究(炎症)开辟新的方向 微生物功能的调节)，而且还提供新的靶标(组织特定的微生物传感和 微生物促进疾病的活性)和用于治疗和 预防结直肠癌。

Summary: During the last funding cycle, we demonstrated that specific microbial activities are important for development of CRC, for example the presence of the pathogenic pks gene island, in certain E.coli of the B2 group, is responsible for the synthesis of the secondary metabolite colibactin (Arthur, J.C., et al. (2012), Science 338(6103), 120–123). In addition, we recently observed a correlation between the presence of hydrogen sulfide (H2S)-producing bacteria (HSPB) and the severity of new onset Crohn's disease (CD) in a pediatric population (Mottawea, W., et al, 2016. Nat Commun 7, 1–14.). Our long-term goal is to determine how bacteria-host interaction influences the development of colitis-associated CRC. The objective of the present competitive renewal is to determine how the host and environmental factors regulate the carcinogenic potential of bacteria. The central hypothesis of this project is that host-derived signaling modulates bacterial-generated metabolites to influence carcinogenesis. The rationale for the proposed research is that once we understand the interplay between bacteria and the host, it would be possible to target specific activity and thus development of colitis- associated CRC. We plan to test our central hypothesis and fulfill the overall objective of this application with the following specific aims. Aim 1. Define inflammatory requirement necessary for bacteria-induced CRC in Il10-/-;Apcmin/+ mice. Aim 2. Establish temporal mechanism implicated in bacteria-induced CRC in Il10-/-;Apcmin/+ mice. Aim 3. Determine microbial responses and CRC development following cell type-specific alteration of of MYD88 signaling in Il10-/- mice. The results will potentially not only open new directions of colorectal cancer research (inflammation modulation of microbial functions) but also provide novel targets (tissue-specific microbial sensing and microbial disease-promoting activity) and means (anti-inflammatory and anti-microbial agents) for treating and preventing colorectal cancer.