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

基本信息

批准号：
10746882
负责人：
Yaohua Yang
金额：
$ 24.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746882
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 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

项目摘要

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.

项目概要人们越来越认识到微生物群失调与结直肠肿瘤有关，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的存在，例如具核梭杆菌和脆弱拟杆菌，已被证实与结直肠肿瘤的发生和进展有关。同时，异常的DNA甲基化和基因表达模式是结直肠肿瘤的标志。因此，要在两者之间建立直接的因果关系肠道微生物组和结直肠肿瘤之间存在关联，因此确定肠道微生物组是否以及如何影响至关重要影响结肠组织中的 DNA 甲基化组和转录组。精心设计的基于人群的研究研究微生物组与宿主的相互作用将为结直肠肿瘤的病因学提供新的线索。期间在过去的 20 年里，我的导师团队建立了两项大型的基于人群的研究，田纳西州结直肠息肉研究（TCPS，P50CA95103 的一部分，PI：Zheng）和南方社区队列研究（SCCS，U01CA202979，PI：Blot、Zheng 和 Shrubsole）。在此，我提出一项多组学研究利用这些大型研究的独特资源来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联腺瘤组织（N=200）。对于目标 2，我将评估微生物组在以下关联中的中介作用：已知的 CRC 危险因素，例如肥胖和不健康的饮食模式，与 DNA 甲基化相关和结直肠腺瘤组织中的基因表达（N=200）。在R00阶段，对于目标3，我会进一步评估其他结直肠腺瘤组织 (N=439) 中 K99 期的结果并寻找通过结合结直肠腺瘤组织的所有数据（N=639）发现新的关联和中介。在此外，结直肠腺瘤组织中的发现将在结直肠癌肿瘤组织中进行研究（N=96）。为了目标 4、我将前瞻性研究诊断前肠道微生物组与DNA甲基化的关系结直肠腺瘤组织 (N=139) 和结直肠癌肿瘤组织 (N=96) 以及结直肠癌组织 (N=96) 中的基因表达结直肠腺瘤（139 例和 139 例匹配对照）和 CRC（96 例和 96 例匹配对照）的风险控制）。最后，这些结果将被整合以确定微生物组的潜在途径可能会影响结直肠肿瘤。这些发现将增进我们对微生物组宿主如何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结直肠癌预防。拟议的职业发展奖将帮助我获得以下方面的高级知识流行病学、结直肠癌生物学、微生物学、高级生物信息学和生物统计学，以及以下方面的技能指导和教育学生和初级研究员，帮助我过渡到一名成功的独立调查员。