NATURE AND ROLE OF THE MICROBIOME IN MOUSE MODELS OF COLON CANCER

结肠癌小鼠模型中微生物组的性质和作用

• 批准号: 8167872
• 负责人: Franklin Wayne Outten
• 金额: $ 14.22万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167872
• 关键词: APC gene; Adenomatous Polyposis Coli; Animal Model; Chronic; Colon; Colon Carcinoma; Colonic Neoplasms; Communities; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Disease Progression; Epithelial Cells; Epithelium; Funding; Gastrointestinal tract structure; Genes; Goals; Grant; Health; Human; Inflammation; Inflammatory Response; Institution; Laser Scanning Confocal Microscopy; Malignant Neoplasms; Microbial Biofilms; Mus; Mutate; Mutation; Nature; Play; Population; Relative (related person); Research; Research Personnel; Resources; Risk; Role; Site; Source; Structure; Testing; Translating; Tumor Suppressor Genes; United States National Institutes of Health; Wild Type Mouse; Work; gut microbiota; microbial; microbial community; microbiome; mouse model; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The microbial population associated with the mammalian body, termed the microbiota, can play a key role in human health. Microbial communities resident in the mammalian gut are complex and dynamic. Changes in species composition or relative species abundance in these communities can retard or enhance disease progression in the host. Despite much empirical evidence for its importance, we are only now starting to elucidate the composition of the microbiota and how specific alterations in the microbiota translate into changes in human health. Our long-term goal is to characterize the role of the gut microbiota, especially microbial biofilms, in suppressing or enhancing diseases such as cancer. The objective of this proposal is to determine the role of biofilm-forming microbiota in promoting tumor formation in a mouse model of colon cancer. The central hypothesis for this proposal is that elevated levels and/or altered species composition of microbial biofilms enhances colon cancer progression in the ApcMin mouse model. The ApcMin mouse animal model for colon cancer has an increased risk of tumor development in the gastrointestinal tract due to a mutation in the APC (adenomatous polyposis coli) tumor suppressor gene. The APC gene is also the most frequently mutated gene in sporadic colon tumors in humans. We will identify whether the biofilm species composition or level of biofilm formation is changed in the ApcMin mouse model of colon cancer. Our working hypothesis is that the amount of biofilm and the biofilm species composition is altered in the ApcMin mouse model of colon cancer. We will test this hypothesis by determining if total level of biofilm is increased in ApcMin compared to wild-type mice, characterizing total microbial diversity in our mouse model using 454 pyrosequencing, and by testing if tumor formation is suppressed or enhanced by altering colonic microbial community structure through the complete transfer of microbiota from the colon of a donor mouse (ApcMin or wild-type) to the sterilized colon of acceptor mice. We also will determine if bacterial species specific to the ApcMin or wild-type mouse colon directly alter tumor formation or inflammatory response in the mouse GI tract. Our working hypothesis is that altered colon microbiota enhances cancer progression in the ApcMin mouse model by stimulating a chronic inflammatory response in the colonic epithelium. We will test this hypothesis by determining if ApcMin-specific microbial species co-localize at sites of tumor formation using FISH and confocal laser scanning microscopy, by testing if microbial species specific to the ApcMin mouse induce an inflammatory response in mouse epithelial cells, and by identifying microbial products that alter tumor formation and/or inflammation in the mouse epithelium.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 与哺乳动物身体相关的微生物群，称为微生物群，可以在人类健康中发挥关键作用。哺乳动物肠道中的微生物群落是复杂而动态的。这些群落中物种组成或相对物种丰度的变化可以延缓或增强宿主的疾病进展。尽管有许多经验证据证明其重要性，但我们现在才开始阐明微生物群的组成以及微生物群的特定变化如何转化为人类健康的变化。我们的长期目标是表征肠道微生物群，特别是微生物生物膜在抑制或增强癌症等疾病中的作用。该提案的目的是确定生物膜形成微生物群在结肠癌小鼠模型中促进肿瘤形成的作用。该提议的中心假设是，微生物生物膜的水平升高和/或物种组成改变会增强ApcMin小鼠模型中的结肠癌进展。由于APC（结肠腺瘤性息肉病）肿瘤抑制基因的突变，用于结肠癌的ApcMin小鼠动物模型在胃肠道中具有增加的肿瘤发展风险。APC基因也是人类散发性结肠肿瘤中最常见的突变基因。我们将确定在结肠癌的ApcMin小鼠模型中生物膜种类组成或生物膜形成水平是否改变。我们的工作假设是，生物膜的量和生物膜种类组成在结肠癌的ApcMin小鼠模型中改变。我们将通过确定与野生型小鼠相比，ApcMin中生物膜的总水平是否增加，使用454焦磷酸测序表征我们的小鼠模型中的总微生物多样性，并通过测试通过改变结肠微生物群落结构是否抑制或增强肿瘤形成来测试这一假设。 将微生物群从供体小鼠（ApcMin或野生型）的结肠转移到受体小鼠的灭菌结肠。我们还将确定ApcMin或野生型小鼠结肠特异性的细菌种类是否直接改变小鼠胃肠道中的肿瘤形成或炎症反应。我们的假设是结肠改变 在ApcMin小鼠模型中，微生物群通过刺激结肠上皮中的慢性炎症反应来增强癌症进展。我们将通过使用FISH和共聚焦激光扫描显微镜确定ApcMin特异性微生物物种是否共定位于肿瘤形成部位来检验这一假设， ApcMin小鼠特异性微生物物种诱导小鼠上皮细胞中的炎症反应，并通过鉴定改变小鼠上皮中肿瘤形成和/或炎症的微生物产物。