Dissecting roles of microbiome-host interactions in colorectal neoplasia etiology using multi-omics data

使用多组学数据剖析微生物组与宿主相互作用在结直肠肿瘤病因学中的作用

• 批准号: 10324580
• 负责人: Yaohua Yang
• 金额: $ 12.12万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324580
• 关键词: Aberrant DNA Methylation; Affect; Bacteroides fragilis; Bioinformatics; Biometry; Cancer Biology; Cancer Etiology; Carcinogenesis Mechanism; Cell Line; Cessation of life; Cohort Studies; Colon; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Colorectal Polyp; Communities; DNA; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Dietary Practices; Epidemiology; Etiology; Fusobacterium nucleatum; Gene Expression; Gene Expression Profile; Human; K-Series Research Career Programs; Knowledge; Light; Link; Malignant Neoplasms; Mediation; Mentors; Microbiology; Multiomic Data; Obesity; Parents; Participant; Pathway interactions; Patients; Phase; Play; Population Study; Preparation; Prospective cohort study; Research Personnel; Resources; Risk; Risk Factors; Role; Students; Tennessee; Tissue Sample; Tissues; Training; Tumor Tissue; United States; adenoma; cohort; colon carcinogenesis; colorectal cancer prevention; colorectal cancer risk; design; dysbiosis; epidemiology study; fecal microbiome; gut microbes; gut microbiome; gut microbiota; host microbiome; improved; methylome; microbiome; mouse model; multiple omics; novel; prospective; skills; stool sample; tool; transcriptome; translational potential; tumor growth

PROJECT SUMMARY Microbiome dysbiosis has been increasingly recognized to be associated with colorectal neoplasia, including colorectal adenoma and colorectal cancer (CRC). Disturbances of the gut microbial community, as well as the presence of specific gut microbes, such as Fusobacterium nucleatum and Bacteroides fragilis, have been linked to the initiation and progression of colorectal neoplasia. Meanwhile, aberrant DNA methylation and gene expression patterns are hallmarks of colorectal neoplasia. Hence, to establish a direct and causal link between the gut microbiome and colorectal neoplasia, it is crucial to determine whether and how the gut microbiome affects the DNA methylome and transcriptome in colon tissues. A well-designed population-based study investigating microbiome-host interplays would shed new light on the etiology of colorectal neoplasia. During the past ~20 years, my mentor's team has established two large population-based studies, the Tennessee Colorectal Polyp Study (TCPS, part of the P50CA95103, PI: Zheng) and the Southern Community Cohort Study (SCCS, U01CA202979, PIs: Blot, Zheng and Shrubsole). Herein, I propose a multi-omics study leveraging the unique resources from these large studies to systematically evaluate the impact of the gut microbiome on DNA methylome and transcriptome in human colorectal neoplasia. In the K99 phase, for Aim 1, I will investigate the associations of microbiome with DNA methylation and gene expression in colorectal adenoma tissues (N=200). For Aim 2, I will evaluate the mediatory roles of microbiome on the associations of known CRC risk factors, such as obesity and unhealthy dietary patterns, in association with DNA methylation and gene expression in colorectal adenoma tissues (N=200). In the R00 phase, for Aim 3, I will further evaluate the findings from the K99 phase in additional colorectal adenoma tissues (N=439) and search for novel associations and mediations through combining all data of colorectal adenoma tissues (N=639). In addition, the findings in colorectal adenoma tissues will be investigated in CRC tumor tissues (N=96). For Aim 4, I will prospectively investigate the relationship of the pre-diagnostic gut microbiome with DNA methylation and gene expression in colorectal adenoma tissues (N=139) and CRC tumor tissues (N=96), as well as with risks of colorectal adenoma (139 cases and 139 matched controls) and CRC (96 cases and 96 matched controls). Finally, these results will be integrated to identify potential pathways through which the microbiome might impact colorectal neoplasia. The findings will improve our understanding of how the microbiome-host interactions impact colorectal neoplasia development and have translational potential to develop new tools for CRC prevention. The proposed career development award will help me gain advanced knowledge of epidemiology, CRC biology, microbiology, advanced bioinformatics and biostatistics, as well as skills in mentoring and educating students and junior fellows, for my transition to a successful independent investigator.

项目摘要 越来越多的人认识到微生物群失调与结直肠肿瘤相关，包括 结直肠腺瘤和结直肠癌（CRC）。肠道微生物群落的紊乱，以及 特定肠道微生物（例如具核梭杆菌和脆弱拟杆菌）的存在已被证实 与结直肠肿瘤的发生和发展有关。与此同时，异常的DNA甲基化和基因 表达模式是结肠直肠瘤形成的标志。因此，要建立直接的因果关系， 肠道微生物组和结直肠肿瘤，关键是要确定肠道微生物组是否以及如何 影响结肠组织中的DNA甲基化组和转录组。一项精心设计的基于人群的研究 研究微生物组-宿主相互作用将为结肠直肠肿瘤的病因学提供新的线索。期间 在过去的20年里，我的导师的团队已经建立了两个大型的基于人群的研究，田纳西州的研究， 结直肠息肉研究（TCPS，P50 CA 95103的一部分，PI：Zheng）和南方社区队列 研究（SCCS，U 01 CA 202979，PI：Blot、Zheng和Shrubsole）。在此，我提出了一个多组学研究， 利用这些大型研究的独特资源，系统地评估肠道的影响， 微生物组对人类结直肠肿瘤DNA甲基化组和转录组的影响。在K99阶段，对于Aim 1，我将研究结直肠中微生物组与DNA甲基化和基因表达的关系 腺瘤组织（N=200）。对于目标2，我将评估微生物组在以下方面的中介作用： 已知的CRC风险因素，如肥胖和不健康的饮食模式，与DNA甲基化相关 结直肠腺瘤组织中的基因表达（N=200）。在R 00阶段，对于目标3，我将进一步 在其他结直肠腺瘤组织（N=439）中评价K99期的结果，并搜索 通过结合结直肠腺瘤组织（N=639）的所有数据，发现了新的关联和中介。在 此外，将在CRC肿瘤组织（N=96）中研究结直肠腺瘤组织中的发现。为宗旨 4，我将前瞻性地研究诊断前肠道微生物组与DNA甲基化的关系 和结直肠腺瘤组织（N=139）和CRC肿瘤组织（N=96）中的基因表达，以及 结直肠腺瘤（139例和139例匹配对照）和结直肠癌（96例和96例匹配对照 对照）。最后，这些结果将被整合，以确定潜在的途径，通过这些途径，微生物组 可能会影响结肠直肠肿瘤。这些发现将提高我们对微生物宿主 相互作用影响结直肠肿瘤的发展，并具有开发新工具的转化潜力， 预防CRC。建议的职业发展奖将帮助我获得先进的知识， 流行病学，CRC生物学，微生物学，先进的生物信息学和生物统计学，以及技能， 指导和教育学生和初级研究员，为我过渡到一个成功的独立调查员。