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：
10359959
负责人：
Tengteng Wang
金额：
$ 17.23万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359959
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 Collaborations Collection Cross-Sectional Studies Data Data Analyses Data Set Development Diagnosis Environment Epidemiology Estrogens Etiology Event Exogenous Hormone Therapy Feces Fibrinogen First Births Fostering Future Goals High Risk Woman Homeostasis Hormonal Hormonal Risk Factor Hormones Hospitals Human Microbiome Intervention Knowledge Lesion Light Link Liquid Chromatography Measurement Mediating Menopause 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 base biomedical scientist breast pathology career cohort disease diagnosis disorder risk disorder subtype experience fecal microbiome gut microbes gut microbiome gut microbiota high risk hormone therapy innovation malignant breast neoplasm 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.

项目概要/摘要该项目的总体目标是确定肠道微生物组在良性乳腺疾病病因学中的作用（BBD），从而揭示了其与乳腺癌的发病机制。美国有五名女性被诊断患有 BBD，这是一种公认的乳腺癌风险指标。 BBD 与乳腺癌具有相同的激素相关危险因素，但其潜在机制却存在关联。激素因素和乳腺疾病之间的关系尚不清楚。新出现的证据表明肠道微生物群可能与激素因素有关。通过影响全身雌激素稳态，显着参与乳腺疾病。支持这样的假设：肠道微生物组是乳腺疾病的关键参与者，并且它可能介导然而，尚无研究系统地研究激素危险因素与 BBD 之间的关联。 Wang 博士提议首先测试 BBD 上的肠道微生物组及其代谢组。她将利用特征明确的护士健康研究 II 中嵌入的子研究来进行假设。在目标 1 (K99) 中，她将测试三个具体目标，以确定肠道微生物组成的潜在差异。在目标 2 (R00) 中，她将研究约 1800 名参与者中各种荷尔蒙因素造成的功能变化。描述肠道微生物组组成与高风险、增殖亚型之间的关联在一项带有乳腺活检样本收集的巢式病例对照研究 (N=300) 中，她将进行 BBD。结合肠道微生物组的功能读数、粪便代谢组学来估计相关性在同一巢式病例对照研究中，研究了微生物代谢组学特征和 BBD 之间的关系。宏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通过整合宏基因组学和代谢组学，她将全面研究分类学。直接参与 BBD 的肠道微生物群落的组成和功能潜力，以及肠道微生物组在激素因素-BBD 关联中的潜在中介作用。拟议的研究可能为新型个性化 BBD 和乳腺癌预防铺平道路王博士认为，女性的荷尔蒙水平和肠道微生物组的潜在调节作用决定了她们的风险。研究目标得到了针对她的两个培训目标的全面培训计划的支持：1）获得培训并将先进的生物信息分析应用于大型微生物组宏基因组和代谢组学数据集； 2) 发展 BBD 流行病学、病因学、病理学和激素决定因素的高级知识布莱根妇女医院的培训环境促进了乳腺癌的发病机制。生产力以及与世界一流生物医学科学家的合作，她组建了一个多学科的团队指导团队包括 BBD、人类微生物组、生物信息学、激素因素、该 K99/R00 奖项将帮助她获得乳腺病理学和乳腺癌流行病学方面的知识和知识。有效从事独立乳腺癌调查员职业所需的经验。