Optimization of Antibiotics in Mothers and their Breastfed Infants Using Pharmacomicrobiomic and Metabolomic Analyses

利用药物微生物组学和代谢组学分析优化母亲及其母乳喂养婴儿的抗生素

• 批准号: 10487493
• 负责人: Lars Bode
• 金额: $ 125万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487493
• 关键词: Address; Ampicillin; Analytical Chemistry; Antibiotic Prophylaxis; Antibiotic Therapy; Antibiotics; Basic Science; Biological Assay; Breast Feeding; Breastfed infant; Centers of Research Excellence; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Sciences; Collection; Cytochrome P450; Data; Data Science; Data Scientist; Development; Drug Kinetics; Enrollment; Ensure; Enzymes; Exposure to; Face; Faculty; Fostering; Growth and Development function; Hepatic; High Pressure Liquid Chromatography; Human; Human Milk; Immune; Immune response; Infant; Infection; Infrastructure; Laboratories; Lead; Leadership; Mass Spectrum Analysis; Metabolic; Milk; Mission; Molecular; Mothers; National Institute of Child Health and Human Development; Near-Infrared Spectroscopy; Neonatal; Nutritional; Oligosaccharides; Outcome; Performance; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Pneumococcal vaccine; Productivity; Protocols documentation; Public Health; Research; Research Infrastructure; Research Methodology; Research Personnel; Research Project Grants; Resources; Role; Sampling; Serum; Skin; Source; Stress; Technical Expertise; Technology; Therapeutic; Therapeutic Human Experimentation; Training; Validation; cohort; drug metabolism; enzyme activity; experience; fundamental research; immune function; infant monitoring; infant outcome; innovation; metabolome; metabolomics; microbiome; milk microbiome; mouse model; non-invasive monitor; novel; operation; pathogen; pediatric pharmacology; pharmacometrics; physiologic model; programs; response; training opportunity

PROJECT SUMMARY The UC San Diego MPRINT CET, entitled “Optimization of Antibiotics in Mothers and Their Breastfed Infants Using Pharmacomicrobiomic and Metabolomic Analyses”, brings together a team of highly experienced and proven collaborative investigators with leadership roles in maternal and pediatric clinical pharmacology, fundamental research methods and technologies. Across its highly integrated and synergistic components, the UCSD MPRINT CET addresses critical barriers in maternal-infant pharmacology regarding (1) the pharmacokinetics of infant exposure to maternal antibiotic treatment via breastmilk or close contact, (2) the impact of maternal antibiotic therapy or prophylaxis on establishment of the normal infant microbiome and gut metabolome, (3) potential downstream effects of such antibiotic exposure on infant immune function and hepatic cytochrome P450 drug metabolizing enzymes, and (4) the pivotal role of breast milk both as a conduit for antibiotic transfer and source of beneficial human/mammalian milk oligosaccharides (HMOs/MMOs) that may support microbiome and immune integrity in face of antibiotic stress. The successful operation and outcome of our MPRINT CET is accomplished through 3 Projects (Clinical, Basic Science and Data Science) an Administrative Core and two Technology Cores, the Milk Analytics Core (MAC) and Pharmacometrics and Analytical Chemistry Core (PACC). In the Clinical Project “Antibiotic Treatment in Breastfeeding Mothers: Effects on Milk, Microbiome, and Infant Outcomes”, we have proven expertise and infrastructure and access to a high enrolling maternal-infant clinical cohort to study how maternal antibiotics alter breast milk composition and impact infant outcomes in clinical meaningful ways. In the Basic Science Project “The Impact of Ampicillin and Breast Milk Oligosaccharides on the Infant Microbiome and Immune Functions”, we leverage extensive experience in mouse models of neonatal host-pathogen interactions to probe functional effects of ampicillin and MMOs on infant immune function, including a novel cross-fostering strategy with wild-type and MMO-deficient mothers. In our Data Science Project “Impact of Maternal Antibiotics on the Breastfeeding Infant Microbiome and Metabolome”, we deploy advanced MS technology, non-invasive sampling and innovative molecular networking analytics in a cutting-edge study of the impact of breast milk antibiotic exposure on the infant microbiome, metabolome and hepatic Cyp enzymes. The MAC provides milk collection protocols and kits, near infrared spectroscopy and HPLC, HMO/MMO and nutritional composition analysis, and new assay validation expanding our MPRINT CET analytical capabilities, while the PAC develops and validates novel quantitative assays and physiologic and semi-physiologic models to describe and predict maternal and infant antibiotic PK during breastfeeding. Our Administrative Core oversees integration and performance of our research projects/cores and their milestones, connecting them to the national MPRINT CET HUB and unique training/pilot projects.

项目概要 加州大学圣地亚哥分校 MPRINT CET，题为“母亲及其母乳喂养婴儿的抗生素优化” 使用药物微生物组学和代谢组学分析”，汇集了一支经验丰富且 在孕产妇和儿科临床药理学领域具有领导作用的经过验证的合作研究人员， 基础研究方法和技术。通过其高度集成和协同的组件， UCSD MPRINT CET 解决了母婴药理学方面的关键障碍：(1) 婴儿通过母乳或密切接触接触母体抗生素治疗的药代动力学，(2) 母体抗生素治疗或预防对正常婴儿微生物组和肠道建立的影响 代谢组，（3）此类抗生素暴露对婴儿免疫功能和肝脏的潜在下游影响 细胞色素 P450 药物代谢酶，以及 (4) 母乳作为导管的关键作用 抗生素转移和有益人/哺乳动物乳寡糖 (HMO/MMO) 的来源，可能 面对抗生素应激，支持微生物组和免疫完整性。手术的成功及效果 我们的 MPRINT CET 通过 3 个项目（临床、基础科学和数据科学）完成 管理核心和两个技术核心，即牛奶分析核心 (MAC) 和药理学 分析化学核心（PACC）。在临床项目“母乳喂养母亲的抗生素治疗：效果”中 “关于牛奶、微生物组和婴儿结局”，我们拥有经过验证的专业知识和基础设施，并且能够获得高水平的 招募母婴临床队列研究母体抗生素如何改变母乳成分和 以临床有意义的方式影响婴儿的结局。在基础科学项目“氨苄青霉素和 母乳低聚糖对婴儿微生物组和免疫功能的影响”，我们利用广泛的 在新生儿宿主-病原体相互作用的小鼠模型中探索氨苄西林和 MMO 对婴儿免疫功能的影响，包括与野生型和 MMO 缺陷型的新型交叉培养策略 妈妈们。在我们的数据科学项目“母体抗生素对母乳喂养婴儿微生物组的影响和 Metabolome”，我们部署先进的 MS 技术、非侵入性采样和创新的分子网络 母乳抗生素暴露对婴儿微生物组影响的前沿研究中的分析， 代谢组和肝 Cyp 酶。 MAC 提供近红外牛奶收集方案和套件 光谱学和 HPLC、HMO/MMO 和营养成分分析，以及新的测定验证扩展 我们的 MPRINT CET 分析能力，而 PAC 开发和验证新颖的定量分析和 用于描述和预测孕产妇和婴儿抗生素 PK 的生理和半生理模型 哺乳。我们的行政核心负责监督我们研究项目/核心的整合和绩效 以及他们的里程碑，将他们与国家 MPRINT CET 中心和独特的培训/试点项目联系起来。