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

基本信息

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.
这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的, 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量, 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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促进宿主的疾病进展。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来测试该假设,使用454焦磷酸测序来表征我们的小鼠模型中的总微生物多样性,通过从供体小鼠的结肠完全转移微生物群来改变结肠微生物群落结构(ApcMin或野生型)至受体小鼠的无菌结肠。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。我们的工作假设是,改变的结肠微生物群通过刺激结肠上皮中的慢性炎症反应来增强ApcMin小鼠模型中的癌症进展。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,通过测试ApcMin小鼠特异性微生物物种是否诱导小鼠上皮细胞中的炎症反应,以及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来测试这一假设。

项目成果

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Franklin Wayne Outten其他文献

Franklin Wayne Outten的其他文献

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{{ truncateString('Franklin Wayne Outten', 18)}}的其他基金

7th International Conference on Fe-S Cluster Biogenesis and Regulation
第七届铁硫簇生物发生与调控国际会议
  • 批准号:
    8529798
  • 财政年份:
    2013
  • 资助金额:
    $ 14.15万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    7927963
  • 财政年份:
    2009
  • 资助金额:
    $ 14.15万
  • 项目类别:
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:
    7959764
  • 财政年份:
    2009
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    7302863
  • 财政年份:
    2007
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    7462244
  • 财政年份:
    2007
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    7803616
  • 财政年份:
    2007
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    7614249
  • 财政年份:
    2007
  • 资助金额:
    $ 14.15万
  • 项目类别:
Characterization of the Suf Fe-S Cluster Biosynthesis Pathway Under Stress
胁迫下 Suf Fe-S 簇生物合成途径的表征
  • 批准号:
    8061980
  • 财政年份:
    2007
  • 资助金额:
    $ 14.15万
  • 项目类别:

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