Antibiotic disruption of the gut microbiome and immune response in neonatal late-onset sepsis

抗生素对新生儿迟发性脓毒症肠道微生物组和免疫反应的破坏

基本信息

批准号：
10662451
负责人：
DREW Joel SCHWARTZ
金额：
$ 16.35万
依托单位：
WASHINGTON UNIVERSITY
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：
2021-08-24 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662451
关键词：
Achievement Adult Advisory Committees Age Antibiotic Resistance Antibiotic Therapy Antibiotic-resistant organism Antibiotics Award Bacteremia Binding Bioinformatics Biological Markers Biological Response Modifiers Birth Bladder Cells Cessation of life Clinical Colon Combined Antibiotics Communicable Diseases Computer Models Computing Methodologies Development Disease Doctor of Philosophy Dose Educational workshop Environment Escherichia coli Feces Flow Cytometry Funding Future Germ-Free Gnotobiotic Goals Grant Gut Mucosa Hospitalization Human Immune Immune response Immunoglobulin A Immunologic Markers Immunologics Incidence Infant Infection Inflammatory International Invaded K-Series Research Career Programs Lead Learning Life Lymphocyte Medical Mentors Mentorship Metadata Modeling Mucosal Immune Responses Mucous Membrane Mus Neonatal Neonatal Intensive Care Units Organism Pathogen detection Pediatric Hospitals Pediatrics Peripheral Physicians Predisposition Research Research Personnel Resources Risk Assessment Risk Factors Sampling Scientist Structure Technical Expertise Testing Training Training Programs Universities Urinary tract infection Uropathogenic E. coli Washington Writing adverse outcome antimicrobial biomarker identification clinical heterogeneity clinical training clinically relevant cohort colon bacteria colonization resistance commensal bacteria cytokine dysbiosis gut microbiome host microbiome humanized mouse late onset sepsis medical schools microbial microbial composition microbiome microbiome analysis microbiome composition microbiome sequencing microbiota modifiable risk mortality mouse model neonatal human neonatal infection neonatal mice neonate novel pathogen pathogenic bacteria peripheral blood predictive marker predictive modeling preterm newborn prevent pup repository resistance gene responsible research conduct septic patients skills symposium

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to describe a five-year training and mentorship plan to prepare Drew Schwartz, MD, PhD to become an independent physician-scientist investigator studying the effects of antibiotics on the preterm neonatal microbiome and host response. Dr. Schwartz obtained combined MD and PhD degrees in the Medical Scientist Training Program at Washington University School of Medicine in St. Louis where he studied how uropathogenic E. coli invade bladder cells to cause severe urinary tract infections. After clinical training in Pediatrics and Infectious Diseases at Washington University School of Medicine and St. Louis Children’s Hospital, he joined the lab of Dr. Gautam Dantas, PhD, a renowned expert on the microbiome and antibiotic resistance. Using fecal samples from an established repository of over 70,000 stools from hospitalized neonates, Dr. Schwartz developed a novel gnotobiotic mouse model of infant microbiome development and disruption. He colonizes germ-free dams with neonatal stool and treats microbiota-humanized pups with clinically relevant doses of antibiotics. He has identified that specific microbiome-antibiotic combinations result in mouse death concomitant with microbiome disruption and immune dysregulation. The central hypothesis is that antibiotic treatment predisposes infants with certain microbiome and resistome compositions to either bacteremic or culture-negative late-onset sepsis. The specific aims of the proposal are to: 1) Define the effects of early-life antibiotics on human infant microbiome maturation, gut mucosal immune response, and vulnerability to bacteremia, and 2) Determine microbial and immune mechanisms of bacteremic and culture-negative late-onset sepsis in a neonatal microbiome-humanized mouse model. The proposed studies will utilize microbiome sequencing, flow cytometry, host immune profiling, and computational modeling to identify modifiable risk factors to refine antibiotic prescribing in the neonatal intensive care unit with the overall goal of reducing incidence and mortality from late-onset sepsis. The mentor, Dr. Dantas, will primarily oversee the project providing training on microbiome analysis, resistome sequencing, and bioinformatic modeling. Dr. Schwartz has assembled an advisory committee with expertise on neonatal infections, antibiotic treatment, gut microbiome development and disruption, and mucosal and peripheral immune response to commensal and pathogenic bacteria. The training plan incorporates achievement of technical expertise, grant writing skills, responsible conduct of research, and mentorship through one-on-one learning, University-sponsored workshops, and presentation and workshops at international conferences. Washington University School of Medicine is the ideal training environment given its extensive track record, outstanding resources, commitment to physician scientists, and necessary expertise to complete the proposed research. This K08 award will provide the necessary skills and resources that Dr. Schwartz requires to become a successful physician scientist whose lab studies the infant microbiome host interface.

项目摘要/摘要该建议的目的是描述一项为期五年的培训和心态计划，以准备医学博士Drew Schwartz 博士成为研究抗生素对早产的影响的独立身体科学家研究者新生儿微生物组和宿主反应。 Schwartz博士在医学中获得了MD和PHD的合并圣路易斯华盛顿大学医学院的科学家培训计划，他在那里如何研究肝病大肠杆菌侵入膀胱细胞会引起严重的尿路感染。经过临床培训华盛顿大学医学院和圣路易斯儿童的儿科和传染病医院，他加入了Gautam Dantas博士博士的实验室，该博士是微生物组和抗生素的著名专家反抗。使用来自住院新生儿的70,000多个粪便的已建立存储库中的粪便样品， Schwartz博士开发了一种新型的婴儿微生物组发育和破坏的gnotobiotic小鼠模型。他用新生儿粪便殖民无菌大坝，并以临床相关抗生素剂量。他已经确定特定的微生物组 - 抗生素组合导致小鼠死亡与微生物组的破坏和免疫失调有关。中心假设是抗生素治疗使婴儿患有某些微生物组和抗抗性组成分，或文化阴性晚期败血症。该提案的具体目的是：1）定义早期的影响人类婴儿微生物组成熟，肠粘膜免疫响应和脆弱性的抗生素细菌血症以及2）确定细菌和培养性阴性的微生物和免疫力学新生儿微生物组人类化的小鼠模型中的败血症。拟议的研究将利用微生物组测序，流式细胞仪，宿主免疫分析和计算建模，以识别可修改的风险因素在新生儿重症监护病房中完善抗生素处方，以减少事件和败血症的死亡率。导师Dantas博士将主要监督提供有关的项目微生物组分析，抵抗组测序和生物信息学建模。 Schwartz博士组装了咨询委员会具有新生儿感染，抗生素治疗，肠道微生物组发展和对共生和致病细菌的破坏，粘膜和外周免疫响应。培训计划纳入了技术专长，授予写作技巧，负责任的研究的成就以及通过一对一的学习，大学赞助的讲习班以及演讲和讲习班的遗产国际会议。华盛顿大学医学院是理想的培训环境广泛的往绩，出色的资源，对物理科学家的承诺以及必要的专业知识完成拟议的研究。该K08奖将为博士提供必要的技能和资源。施瓦茨（Schwartz）要求成为一名成功的物理科学家界面。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Everything but the Kitchen Sink: An Analysis of Bacterial and Chemical Contaminants Found in Syringe Residue From People Who Inject Drugs.

DOI：
10.1093/ofid/ofad628
发表时间：
2024-01
期刊：
Open forum infectious diseases
影响因子：
4.2
作者：
通讯作者：

Impact of international travel and diarrhea on gut microbiome and resistome dynamics.

DOI：
10.1038/s41467-022-34862-w
发表时间：
2022-12-05
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Boolchandani, Manish;Blake, Kevin S.;Tilley, Drake H.;Cabada, Miguel M.;Schwartz, Drew J.;Patel, Sanket;Morales, Maria Luisa;Meza, Rina;Soto, Giselle;Isidean, Sandra D.;Porter, Chad K.;Simons, Mark P.;Dantas, Gautam
通讯作者：
Dantas, Gautam