Defining the changing microbiome composition and host-microbe mechanistic effects following Apc inactivation during colorectal cancer pathogenesis

定义结直肠癌发病过程中 Apc 失活后微生物组组成的变化和宿主微生物机制效应

基本信息

  • 批准号:
    10750676
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-16 至 2026-09-15
  • 项目状态:
    未结题

项目摘要

Project Summary Globally, colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women and is projected to increase by 70% in the next 20 years. One of the earliest initiating events of CRC is mutation of adenomatous polyposis coli (APC), a tumor suppressor gene. This mutation initiates the gradual progression from normal proliferating colon epithelial cells (CECs) to dysplastic lesions, to the eventual formation of tumors, known as adenomas. Somatic APC mutations occur in >80% of sporadic CRCs. Growing evidence demonstrates that factors within the local microenvironment can significantly influence cancer risk and onset. One key characteristic of the colon adenomatous environment is an imbalanced microbiome. Disruption in the makeup of these microbiota, known as dysbiosis, is related to many diseases, including colitis, inflammatory bowel disease, and CRC. While dysbiosis contributes to promoting adenoma progression and CRC, whether APC mutation triggers changes in the local microenvironment to facilitate tumor progression and microbiome dysbiosis remains largely unknown. Using an inducible murine model of CEC Apc truncation, our lab found that Apc inactivation and subsequent colon tumorigenesis results in microbiome dysbiosis and outgrowth of pathogenic species, further, associated with increased bacterial mucosal adherence. This proposal aims to define the timing and mechanisms by which the early microbiome changes following Apc inactivation. We hypothesize that Apc loss alters the microenvironment to cause early loss of commensal species and provides a habitat for pathogenic outgrowth and pro-carcinogenesis. We will test our hypothesis through the following aims. Aim 1: Defining the effects of Apc inactivation on the composition, spatial/temporal dynamics, and tumorigenic potential of the host microbiome. Using 16S rRNA amplicon sequencing and microbiology, I will identify early microbiome changes following Apc loss during gradual colon tumorigenesis and will determine if this differs by colon region. I will use germ-free models to evaluate if the changing microbiome is sufficient to induce colon tumorigenesis. Aim 2: Identifying the mechanism(s) by which Apc inactivation contributes to microbiome dysbiosis and the expansion of pathogenic species. I will utilize transcriptomics and metabolomics to examine changes in metabolic pathways and gene regulation in association with changes in microbiome composition and timing of Apc inactivation. This research will provide novel insights into the events occurring upon Apc mutation and the crosstalk between mutated CECs and the local microbiome.
项目摘要 在全球范围内,结直肠癌(CRC)是男性和女性癌症相关死亡的第二大原因 预计在未来20年内将增长70%。CRC最早的起始事件之一是 腺瘤性结肠息肉病(APC),一种肿瘤抑制基因的突变。这种突变启动了 从正常增殖的结肠上皮细胞(CEC)到发育异常病变,到最终的结肠癌, 形成肿瘤,称为腺瘤。体细胞APC突变发生在>80%的散发性CRC中。增长 有证据表明,局部微环境中的因素可以显著影响癌症风险。 和发病。结肠腺瘤环境的一个关键特征是不平衡的微生物组。 这些微生物群组成的破坏,称为生态失调,与许多疾病有关,包括 结肠炎、炎症性肠病和CRC。虽然生态失调有助于促进腺瘤进展 和CRC,APC突变是否触发局部微环境的变化以促进肿瘤进展 微生物群落失调在很大程度上仍是未知的。使用CEC Apc截短的诱导型鼠模型, 我们的实验室发现,APC失活和随后的结肠肿瘤发生导致微生物群生态失调, 此外,致病物种的生长与细菌粘膜粘附增加有关。这 该提案旨在确定APC后早期微生物组变化的时间和机制 失活我们推测,APC的丢失改变了微环境,导致早期的骨丢失。 物种,并提供了一个栖息地的致病性生长和促癌作用。我们将测试我们的假设 通过以下目标。目的1:确定Apc失活对组成、空间/时间的影响 动力学和宿主微生物组的致瘤潜力。使用16 S rRNA扩增子测序和 微生物学,我将确定在逐渐的结肠肿瘤发生过程中Apc丢失后的早期微生物组变化 并且将确定这是否因结肠区域而不同。我将使用无菌模型来评估 微生物组足以诱导结肠肿瘤发生。目标2:确定APC 失活导致微生物群落生态失调和致病物种的扩张。我会利用 转录组学和代谢组学研究代谢途径和基因调控的变化, 与微生物组组成的变化和Apc失活的时间相关。这项研究将提供 对Apc突变后发生的事件以及突变的CEC与 当地微生物

项目成果

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Lindsey Dzierozynski的其他文献

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