Elucidating the role of gut microbiota in colitis-associated colorectal cancer

阐明肠道微生物群在结肠炎相关结直肠癌中的作用

• 批准号: 10564074
• 负责人: Ru Chen
• 金额: $ 64.91万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564074
• 关键词: Affect; Animal Model; Apoptosis; Bacteria; Bacterial Genes; Bioinformatics; Biological; Biological Models; Biopsy; Cancer Detection; Chronic; Clinical; Clinical Research; Colitis associated colorectal cancer; Colon; Colorectal Cancer; DNA Damage; Development; Disease; Enzymes; Epithelium; Event; Genes; Genomic Instability; Gut Mucosa; Human; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Integration Host Factors; Intestinal Cancer; Investigation; Knowledge; Laboratories; Light; Longitudinal Studies; Malignant Neoplasms; Metabolism; Modeling; Molecular; Mucous Membrane; Mus; Organoids; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Proliferating; Proteome; Proteomics; Rectum; Research; Resources; Risk; Role; Sampling; Signal Pathway; Specimen; Structure; Study models; Surface; System; Systems Biology; Taxonomy; Techniques; Technology; Ulcerative Colitis; Work; cancer therapy; carcinogenesis; colitis associated cancer; colorectal cancer prevention; colorectal cancer risk; design; dextran sulfate sodium induced colitis; dysbiosis; fecal microbiota; gut microbes; gut microbiome; gut microbiota; human microbiota; in vivo; innovation; interest; metaproteomics; microbial; microbial community; microbiome; microbiome composition; microbiota; microbiota profiles; mouse model; mucosal microbiota; new technology; novel diagnostics; novel strategies; novel therapeutic intervention; phosphoproteomics; protein expression; rectal; response; statistics; tool; translational potential; tumor progression; tumorigenic

Abstract Patients with ulcerative colitis (UC), an inflammatory bowel disease (IBD), have an increased risk of developing colitis-associated colorectal cancer (CAC). Human gut microbiome composition has recently been associated with a wide array of diseases, including IBD and colorectal cancer. Studies have shown that gut microbiota could influence colon epithelium to initiate or promote colorectal cancer development directly or indirectly. However, little is known on the structure and function of the microbiota in CAC and how they implicate the development of CAC at the molecular level. In this study, we will investigate the role of microbiota in the development of CAC, as well as the molecular events underlying the interplay of microbiota and host response. The project builds upon our previous studies in examining the genomic instabilities and proteome alterations in the colon epithelium during the pathogenesis of IBD-CAC, and will focus on the mechanistic and functional involvement of the microbiome and their components in the modulation (by protective bacteria) or activation (by tumorigenic bacteria) of CAC development. Specifically, we will investigate the implication of mucosa- associated microbiota in CAC by an integrated approach using three model systems, including clinical specimens (Aim 1), in vitro microbial cultivation and organoid models (Aim 2), and in vivo mouse model (Aim 3). Our integrative, state-of-the-art approach will characterize the composition, functional genes and pathways of the microbiome implicated in CAC, and the impact of microbiota on colon mucosa. By studying the gut microbiota and its interplay with the colon host using novel approaches and cutting-edge technology, our study has significant translational potential that could lead to establishing the gut microbiome as predictors of CAC risk and aid in developing approaches for CAC prevention and detection in IBD patients.

摘要 溃疡性结肠炎（UC）是一种炎症性肠病（IBD）， 结肠炎相关的结肠直肠癌（CAC）。人类肠道微生物组组成最近与 包括炎症性肠病和结肠直肠癌在内的一系列疾病。研究表明，肠道微生物群 可能直接或间接影响结肠上皮细胞启动或促进结直肠癌的发生。 然而，对CAC中微生物群的结构和功能以及它们如何影响CAC的研究却知之甚少。 在分子水平上发展CAC。在这项研究中，我们将研究微生物群在 CAC的发展，以及微生物群和宿主反应相互作用的分子事件。 该项目建立在我们以前的研究，在检查基因组不稳定性和蛋白质组改变， 结肠上皮细胞在IBD-CAC发病过程中的作用，并将重点放在机制和功能上， 微生物组及其组分参与调节（通过保护性细菌）或激活 (by致瘤细菌）的CAC发展。具体来说，我们将研究粘膜的含义- 通过使用三个模型系统的综合方法，包括临床 标本（Aim 1）、体外微生物培养和类器官模型（Aim 2）以及体内小鼠模型（Aim 3）。我们的综合，国家的最先进的方法将特点的组成，功能基因和途径 CAC中涉及的微生物组，以及微生物群对结肠粘膜的影响。通过研究肠道 微生物群及其与结肠宿主的相互作用，使用新的方法和尖端技术，我们的研究 具有显著的转化潜力，可能导致建立肠道微生物组作为CAC的预测因子 在IBD患者中预防和检测CAC的方法。