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

基本信息

批准号：
10309708
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
项目类别：
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/10309708
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

项目摘要

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的高度集成和协同组成部分。 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时支持微生物组和免疫完整性。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) 临床项目“母乳喂养母亲的抗生素治疗：效果” “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在基础科学项目“氨苄西林和氨苄西林的影响”中，以具有临床意义的方式影响婴儿的结局。 “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，包括野生型和 MMO 缺陷型的新型交叉培养策略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”中。 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， MAC 提供近红外乳汁采集方案和试剂盒。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我们的行政核心负责监督我们的研究项目/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/试点项目连接起来。