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

项目总结 微生物组失调已被越来越多地认识到与大肠肿瘤有关，包括 结肠腺瘤和结直肠癌(CRC)。肠道微生物群落的干扰，以及 特定肠道微生物的存在，如核梭杆菌和脆弱类杆菌，已经被 与大肠肿瘤的发生和发展有关。同时，DNA甲基化和基因异常 表达模式是大肠肿瘤的特征。因此，建立直接和因果关系之间的联系 肠道微生物群与大肠肿瘤的关系，关键是要确定肠道微生物群是否以及如何 影响结肠组织中的DNA甲基组和转录组。精心设计的以人群为基础的研究 研究微生物组-宿主的相互作用将为大肠肿瘤的病因学提供新的线索。在.期间 在过去的20年里，我导师的团队已经建立了两项大规模的基于人群的研究，田纳西州 大肠息肉研究(TCPS，P50CA95103的一部分，PI：郑)和南方社区队列 研究(SCCS，U01CA202979，PI：印迹，郑灌木)。在此，我建议进行一项多组学研究 利用这些大型研究的独特资源，系统地评估肠道的影响 大肠肿瘤组织中微生物组DNA甲基组和转录组的研究在K99阶段，对于AIM 1、我将研究微生物组与大肠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 已知的结直肠癌危险因素，如肥胖和不健康的饮食模式，与DNA甲基化有关 结直肠腺瘤组织中的基因表达(N=200)。在R00阶段，对于目标3，我将进一步 评估K99期在其他结直肠腺瘤组织中的发现(N=439)并搜索 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……里面 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)。为了达到目标 4，我将前瞻性地研究诊断前肠道微生物群与DNA甲基化的关系 结直肠腺瘤组织(N=139)和结直肠癌组织(N=96)中的基因表达 结直肠腺瘤(139例和139名配对对照)和结直肠癌(96例和96名配对对照)的风险 控制)。最后，这些结果将被综合起来，以确定微生物组可能通过的途径 可能会影响大肠肿瘤的形成。这些发现将提高我们对微生物群如何宿主的理解 相互作用影响结直肠肿瘤的发展，并具有开发新工具的翻译潜力 CRC预防。拟议的职业发展奖将帮助我获得以下高级知识 流行病学、CRC生物学、微生物学、高级生物信息学和生物统计学，以及 指导和教育学生和初级研究员，为我过渡到一名成功的独立调查员。

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.