Identifying the role of the gut microbiome in the etiology of benign breast disease

确定肠道微生物组在良性乳腺疾病病因学中的作用

基本信息

批准号：
10642675
负责人：
Tengteng Wang
金额：
$ 16.9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642675
关键词：
16S ribosomal RNA sequencing Age Age at Menarche Applications Grants Attention Award Bacteria Bacteroides Benign Bioinformatics Biopsy Breast Breast Cancer Epidemiology Breast Cancer Prevention Breast Diseases Breast biopsy Cancer Etiology Catalogs Cessation of life Classification Collaborations Collection Data Data Analyses Data Set Development Diagnosis Environment Epidemiology Estrogens Etiology Event Exogenous Hormone Therapy Feces First Births Fostering Future Goals High Risk Woman Homeostasis Hormonal Hormonal Risk Factor Hormones Hospitals Human Microbiome Intervention Knowledge Lesion Link Liquid Chromatography Measurement Mediating Mentors Metabolism Metagenomics Methods Morbidity - disease rate Multiomic Data Nested Case-Control Study Nulliparity Nurses Nurses&apos Health Study Oral Contraceptives Participant Pathogenesis Pathologic Pathologist Pathology Pathway interactions Play Productivity Proliferative Type Breast Fibrocystic Change Prospective Studies Reporting Reproductive History Research Research Personnel Retrospective Studies Risk Risk Factors Risk Reduction Role Sample Size Shotguns Strategic vision Taxonomy Testing Tissue Sample Training United States Variant Woman biomedical scientist breast pathology career cohort disease diagnosis disorder risk disorder subtype experience fecal microbiome gut microbes gut microbiome gut microbiota high risk innovation malignant breast neoplasm menopausal hormone therapy metabolome metabolomics metagenomic sequencing microbial microbial community microbial signature microbiome microbiome composition microbiome research microbiota microbiota metabolites mortality multidisciplinary multiple omics novel premalignant programs prospective reproductive risk prediction sample collection small molecule stool sample tandem mass spectrometry

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to identify the role of the gut microbiome in the etiology of benign breast disease (BBD), and thereby shed light on its pathogenesis in relation to breast cancer. Approximately one out of every five women in the United States has been diagnosed with BBD, a well-established risk indicator for breast cancer. BBD share the hormonal-related risk factors with breast cancer. However, the underlying mechanisms linking hormone factors and breast disease are not clear. Emerging evidence suggests that the gut microbiome may be significantly involved in breast disease through the influence on systemic estrogen homeostasis. This evidence supports the hypothesis that the gut microbiome is a key player in breast disease, and it may mediate the associations between hormonal risk factors and BBD. However, no study has systematically studied the role of the gut microbiome and its metabolome on BBD. Dr. Wang proposes to be the first to test this important hypothesis. She will leverage the sub-studies embedded in the well-characterized Nurses’ Health Study II, to test the three specific aims. In Aim 1 (K99), she will identify potential differences in gut microbial composition and functional variation by various hormonal factors among ~1800 participants. In Aim 2 (R00), she will characterize the associations between gut microbiome composition and the high-risk, proliferative subtype of BBD in a nested case-control study (N=300) with breast biopsy sample collection. In Aim 3 (R00), she will incorporate the functional readout of gut microbiome, the fecal metabolomics, to estimate the associations between microbial metabolomic signatures and BBD in the same nested case-control study. Innovative shotgun metagenomic sequencing and semi-targeted metabolomics will be used to discover microbial strains and their metabolites. By integrating metagenomics and metabolomics, she will comprehensively investigate taxonomic composition and functional potential of gut microbial communities that are directly involved in BBD, as well as the potential mediating role of the gut microbiome underlying the hormonal factors-BBD associations. Results from the proposed study may pave the way for novel personalized BBD and breast cancer prevention for high- risk women defined by their hormonal profiles, with the potential modulation of gut microbiome. Dr. Wang’s research aims are supported by a well-rounded training plan tailored to her two training goals: 1) Obtain training and apply advanced bioinformatic analytics to large microbiome metagenomic and metabolomics datasets; and 2) Develop advanced knowledge on hormonal determinants on BBD epidemiology, etiology, pathology, and pathogenesis as it relates to breast cancer. The training environment at Brigham and Women’s Hospital fosters productivity and collaboration with world class biomedical scientists, and she have assembled a multidisciplinary mentoring team that includes leading experts in BBD, human microbiome, bioinformatics, hormonal factors, breast pathology, and breast cancer epidemiology. This K99/R00 award will help her gain the knowledge and experience necessary to effectively pursue her career as an independent breast cancer investigator.

项目摘要/摘要该项目的总体目标是确定肠道微波经在乳腺病病因中的作用（BBD），并被认为阐明了其与乳腺癌有关的发病机理。美国的五名妇女被诊断出患有BBD，这是乳腺癌的良好生命的风险指标。 BBD与乳腺癌共享与荷尔蒙相关的风险因素。激素因素和乳房疾病尚不清楚。通过对全身性估算性埃斯塔斯顿的影响，显着参与乳房疾病。支持肠道微生物组是乳房疾病的关键人物的假设，它可能介导您荷尔蒙风险因素与BBD之间的关联。 BBD上的肠道微生物组及其代谢组。假设。在AIM 1（K99）中测试三个特定目标在AIM 2（R00）中，各种荷尔蒙因素的功能变化。表征肠道微生物组组成与高风险，增生性亚型之间的关联在AIM 3（R00）中，BBD在嵌套的病例对照研究（n = 300）中。结合肠道微生物组的功能读数，粪便代谢组学，以估计关联在相同的壳体病例对照研究中，微生物代谢组的特征和BBD 元基因组测序和半靶向代谢组学将用于发现微生物菌株及其它们的代谢物通过整合宏基因组学和代谢组学，她将全面调查分类学肠道微生物群落的组成和功能潜力直接参与BBD，以及肠道微频率的潜在介导作用是激素因子BBD关联的结果。从支撑研究中，可以为新型的个性化BBD和乳腺癌准备铺平妇女的荷尔蒙特征定义，并具有肠道微生物组的潜在模块化研究目标得到了针对她的两个培训目标量身定制的全面培训计划的支持：1）获得培训并将高级生物信息学分析应用于大型宏基因组和代谢组学数据集； 2）关于BBD流行病学，遗传学，病理学和发病机理与乳腺癌有关。与世界一流的生物医学科学家的生产力和合作，她汇集了多个学院指导团队包括BBD领先的专家，人类微生物组，生物信息学，荷尔蒙因素，荷尔蒙因素，乳腺病理学和乳腺癌流行病学。有效地追求她的护理护理护理癌症调查员所需的经验。