Mechanistic characterization of vaginal microbiome-metabolome associations and metabolite-mediated host inflammation

阴道微生物组-代谢组关联和代谢物介导的宿主炎症的机制特征

基本信息

批准号：
10663410
负责人：
SETH MICHAEL BLOOM
金额：
$ 18.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-17 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663410
关键词：
Address Affect Africa South of the Sahara African Amines Anabolism Anatomy Bacteria Bacterial Physiology Bacterial Vaginosis Bacteriology Biochemical Biogenic Amines Bioinformatics Biological Markers Biology Cadaverine Cell Proliferation Cellular Metabolic Process Chemicals Chemistry Clinical Clinical Markers Collaborations Communicable Diseases Communities Data Development Plans Disease Environment Enzymatic Biochemistry Enzyme Inhibitor Drugs Enzymes Functional disorder General Hospitals Genomics Goals HIV HIV risk Health Imidazole Immune response Immunologics Immunology In Vitro Inflammation Inflammatory Inflammatory Response Knowledge Lactobacillus Link Malignant Neoplasms Malignant neoplasm of cervix uteri Massachusetts Measures Mediating Mediator Medicine Mentors Metabolic Metagenomics Methods Microbial Biofilms Mucositis Mucous Membrane Outcome Pathogenesis Pathogenicity Pathway interactions Physicians Population Premature Birth Prevalence Production Propionates Putrescine Reproducibility Research Research Personnel Role Scientist Site Smell Perception Source South African Symptoms Testing Therapeutic Tissues Training Universities Vagina Vaginal Diseases Validation Woman bacterial community candidate identification candidate marker career career development cohort cytokine diagnostic criteria eIF-5A enzyme activity experience experimental study high volume manufacturing immunoregulation in vivo inhibitor innovation instructor interest medical schools metabolome metabolomics metagenome metatranscriptomics microbial microbiome microbiome composition microbiota multiple omics novel novel therapeutic intervention novel therapeutics pharmacologic potential biomarker prevent reproductive outcome reproductive tract skills targeted treatment translation factor vaginal fluid vaginal microbiome vaginal microbiota

项目摘要

Project Summary/Abstract The vaginal microbiome is associated with important health outcomes, including bacterial vaginosis (BV), preterm birth, HIV risk, and cervical cancer, but mechanisms for these associations are unclear and current microbiome-directed therapies have low efficacy. Metabolome alterations including high-level production of amines like putrescine are a defining feature of BV and a major cause of symptoms, but underlying mechanisms and host responses to BV-associated metabolites including amines are poorly characterized. In preliminary data from a South African cohort with high BV prevalence, 60% of detectable metabolites in vaginal fluid significantly differ between optimal Lactobacillus-dominant bacterial communities and non-optimal non-Lactobacillus- dominant (NLD) communities. Strongly BV- and NLD-associated metabolites included putrescine and imidazole propionate (ImP), both of which are known to have adverse host effects in non-vaginal diseases but whose production and effects remain largely uncharacterized in the genital tract. These results suggest bacteria comprising NLD communities express enzymes that produce these metabolites. The study will (1) characterize metabolome and metagenome composition in additional cohorts to validate findings and identify candidate enzymes for putrescine and ImP production, (2) characterize the enzymes in cultured vaginal bacteria and assess effects of known pharmacologic inhibitors, and (3) assess effects of putrescine and ImP on metabolic and inflammatory host responses and test whether they can be blocked by known host pathway inhibitors. The results will elucidate vaginal metabolome-related pathophysiology and may directly identify candidate therapies. The PI is an Instructor in Medicine at Harvard Medical School and the Division of Infectious Diseases at Massachusetts General Hospital (MGH); in addition to the research plan this proposal includes a five-year career development plan. His career goal is to become an independent physician-scientist investigator studying mechanisms of vaginal microbiome- and metabolome-mediated disease through bacteriologic, biochemical, and immunologic approaches to identify novel therapies. The proposal builds on the PI’s prior experience studying vaginal microbiome dynamics and investigating the physiology of bacterial species within the microbiome. The current proposal significantly expands his scientific scope by investigating microbial determinants of vaginal metabolome composition, identifying host pathways those metabolites affect, and testing pathway inhibitors. He will pursue this research under the guidance of his primary mentor, Dr. Doug Kwon, at the Ragon Institute of MGH, MIT and Harvard and his co-mentor, Dr. Emily Balskus, at the Harvard University Department of Chemistry and Chemical Biology. He will pursue didactic coursework and receive training, guidance, and collaboration from a diverse team of experts. The proposed training provides the PI with a unique skillset and wealth of initial data to facilitate his transition to research independence.

项目概要/摘要阴道微生物群与重要的健康结果相关，包括细菌性阴道病 (BV)、早产、艾滋病毒风险和宫颈癌，但这些关联的机制目前尚不清楚微生物组定向疗法的功效较低，包括高水平产生的代谢组改变。腐胺等胺是 BV 的一个决定性特征，也是症状的主要原因，但其潜在机制初步数据表明，宿主对 BV 相关代谢物（包括胺）的反应尚不清楚。在 BV 患病率较高的南非队列中，阴道液中 60% 的可检测代谢物显着最佳乳杆菌优势细菌群落和非最佳非乳杆菌群落之间存在差异 (NLD) 群落与 BV 和 NLD 相关的代谢物包括腐胺和咪唑。丙酸盐（ImP），已知这两种物质都会对非阴道疾病产生不良宿主影响，但其这些结果表明，生殖道中的细菌的产生和影响在很大程度上仍然未知。包括 NLD 群落表达产生这些代谢物的酶该研究将 (1) 表征。其他队列中的代谢组和宏基因组组成，以验证结果并确定候选者用于生产腐胺和 ImP 的酶，(2) 表征培养的阴道细菌中的酶，以及评估已知药物抑制剂的作用，以及 (3) 评估腐胺和 ImP 对代谢的影响和炎症宿主反应，并测试它们是否可以被已知的宿主途径抑制剂阻断。结果将阐明阴道代谢组相关的病理生理学，并可能直接确定候选疗法。 PI 是哈佛医学院和哈佛医学院传染病科的医学讲师马萨诸塞州综合医院 (MGH)；除了研究计划外，该提案还包括五年的职业生涯他的职业目标是成为一名独立的医师科学家研究人员。阴道微生物组和代谢组介导的疾病的机制通过细菌学、生化和该提案建立在 PI 先前研究经验的基础上。阴道微生物组动力学并研究微生物组内细菌物种的生理学。目前的提案通过研究阴道微生物决定因素显着扩大了他的科学范围代谢组组成，确定代谢物影响的宿主途径，并测试途径抑制剂。将在他的主要导师、Ragon 研究所的 Doug Kwon 博士的指导下进行这项研究 MGH、麻省理工学院和哈佛大学及其共同导师、哈佛大学化学系 Emily Balskus 博士他将学习教学课程并接受培训、指导和合作。拟议的培训为 PI 提供了独特的技能和丰富的初始数据。促进他过渡到独立研究。