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

• 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
• 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' 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

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生物组在良性乳腺疾病病因学中的作用 (BBD)从而阐明其与乳腺癌的发病机制。大约每一个 美国有五名妇女被诊断出患有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生殖相关危险因素。然而，联系的基本机制 激素因素与乳腺疾病关系尚不清楚。新出现的证据表明，肠道微生物组可能是 通过影响全身雌激素稳态而显著参与乳腺疾病。这一证据 支持肠道微生物组是乳腺疾病的关键参与者的假设，它可能介导 激素风险因素与BBD之间的关系。然而，还没有研究系统地研究了 肠道微生物组及其代谢物组对BBD的影响。王博士建议成为第一个测试这一重要的 假说.她将利用嵌入在特征鲜明的护士健康研究II中的子研究， 三个具体目标。在目标1（K99）中，她将确定肠道微生物组成的潜在差异 和功能变化的各种激素因素之间的~1800参与者。在目标2（R 00）中，她将 描述肠道微生物组组成与高风险，增殖亚型之间的关联， 一项采用乳腺活检样本采集的巢式病例对照研究（N=300）中的BBD。在目标3（R 00）中，她将 结合肠道微生物组的功能读数，粪便代谢组学， 在同一巢式病例对照研究中，微生物代谢组学特征与BBD之间存在差异。创新霰弹枪 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 代谢物。通过整合宏基因组学和代谢组学，她将全面研究分类 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子-BBD关联中的潜在介导作用。结果 这项研究可能为新型个性化BBD和乳腺癌预防铺平道路， 风险妇女由他们的激素谱定义，具有肠道微生物组的潜在调节。王医生的 研究目标得到了一个全面的培训计划的支持，该计划针对她的两个培训目标：1）获得培训 并将先进的生物信息学分析应用于大型微生物组宏基因组和代谢组学数据集; 2)发展关于BBD流行病学，病因学，病理学和激素决定因素的先进知识， 发病机制，因为它与乳腺癌有关。布里格姆妇女医院的培训环境 生产力和与世界一流的生物医学科学家的合作，她已经组装了一个多学科的 指导团队包括BBD，人类微生物组，生物信息学，激素因子， 乳腺病理学和乳腺癌流行病学。这个K99/R 00奖项将帮助她获得知识， 经验，以有效地追求她的职业生涯作为一个独立的乳腺癌调查。