Role of Bacteria in Colitis-Associated Colon Cancer

细菌在结肠炎相关结肠癌中的作用

• 批准号: 10618129
• 负责人: Christian Jobin
• 金额: $ 42.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618129
• 关键词: Acute; Address; Animal Model; Anti-Inflammatory Agents; Antibiotics; Antibodies; ApcMin/+ mice; Attention; Attenuated; Bacteria; Bismuth; Childhood; Colitis; Colitis associated colorectal cancer; Colonic Neoplasms; Colorectal Cancer; Communities; Complex; Crohn' s disease; DNA Repair; Development; Environmental Risk Factor; Epithelial Cells; Escherichia coli; Exposure to; Funding; Gene Deletion; Gene Expression; Genes; Genetic; Germ-Free; Gnotobiotic; Goals; Grant; Human; Hydrogen Sulfide; Immune response; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Integration Host Factors; Interdisciplinary Study; Island; Link; Microbial Genetics; Modeling; Mus; Myeloid Cells; Pathogenicity; Pathogenicity Island; Population; Pre-Clinical Model; Predisposition; Qualifying; RNA Sequences; Research; Risk; Role; Sampling; Science; Series; Severities; Signal Transduction; TNF gene; Talents; Technology; Testing; Therapeutic; Tissues; anticancer research; antimicrobial drug; carcinogenesis; carcinogenicity; cell type; colorectal cancer prevention; environmental stressor; genotoxicity; germ free condition; intestinal epithelium; microbial; microbial community; microbial composition; microbial disease; microbial genomics; microbiota; mucosal microbiota; novel; prevent; prophylactic; repaired; response; secondary metabolite; transcriptome sequencing; transmission process; tumor; tumorigenesis

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.

概括： 在上一个融资周期中，我们证明了特定的微生物活动对于 CRC的发展，例如在B2的某些e.coli中存在致病性PKS基因岛 组负责二级代谢物结肠蛋白酶的合成（Arthur，J.C。等（2012），Science，Science 338（6103），120-123）。此外，我们最近观察到硫化氢存在之间的相关性 （H2S） - 产生细菌（HSPB）和小儿种群中新发作的克罗恩病（CD）的严重程度 （Mottawea，W。等，2016。NatCommun 7，1-14。）。我们的长期目标是确定细菌宿主如何 相互作用影响与结肠炎相关的CRC的发展。目前竞争的目标 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。 该项目的中心假设是宿主衍生的信号传导调节细菌生成的代谢产物 影响致癌。拟议研究的理由是，一旦我们了解了互动 在细菌和宿主之间，有可能靶向特定活性，从而发展结肠炎 相关的CRC。我们计划检验我们的中心假设，并通过 遵循特定目标。 AIM 1。定义细菌诱导的IL10 - / - ; APCMIN/+小鼠所必需的炎症需求。 AIM 2。建立在IL10 - / - ; APCMIN/+小鼠中实施的临时机制。 目标3。在细胞类型特异性变化之后确定微生物反应和CRC发育 IL10 - / - 小鼠中的MyD88信号传导。 结果不仅可能开放结直肠癌研究的新方向（炎症 微生物功能的调节），但也提供了新的靶标（组织特异性微生物感应和 微生物疾病活性）和平均（抗炎和抗微生物剂）用于治疗和 防止结直肠癌。

项目成果

Carcinogenesis and therapeutics: the microbiota perspective.

• DOI: 10.1038/nmicrobiol.2017.8
• 发表时间: 2017-02-22
• 期刊: Nature microbiology
• 影响因子: 28.3
• 作者: Tsilimigras MC;Fodor A;Jobin C
• 通讯作者: Jobin C

Structural identification of mouse fecal metabolites of theaflavin 3,3'-digallate using liquid chromatography tandem mass spectrometry.

• DOI: 10.1016/j.chroma.2011.08.056
• 发表时间: 2011-10-14
• 期刊: Journal of chromatography. A
• 作者: Chen H;Parks TA;Chen X;Gillitt ND;Jobin C;Sang S
• 通讯作者: Sang S

Bacteria break barrier to promote metastasis.

• DOI: 10.1016/j.ccell.2021.03.009
• 发表时间: 2021-05-10
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Murota Y;Jobin C
• 通讯作者: Jobin C

Amending microbiota by targeting intestinal inflammation with TNF blockade attenuates development of colorectal cancer.

• DOI: 10.1038/s43018-020-0078-7
• 发表时间: 2020-07
• 期刊: Nature cancer
• 影响因子: 22.7
• 作者: Yang Y;Gharaibeh RZ;Newsome RC;Jobin C
• 通讯作者: Jobin C

Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.

• DOI: 10.1126/science.1191175
• 发表时间: 2010-11-05
• 期刊: Science (New York, N.Y.)
• 作者: Wallace BD;Wang H;Lane KT;Scott JE;Orans J;Koo JS;Venkatesh M;Jobin C;Yeh LA;Mani S;Redinbo MR
• 通讯作者: Redinbo MR