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

项目总结/摘要 该提案的目标是描述一个五年培训和指导计划，以准备德鲁施瓦茨，医学博士， 博士成为一名独立的医生，科学家研究员，研究抗生素对早产儿的影响 新生儿微生物组和宿主反应。Schwartz博士获得医学博士和博士学位 圣路易斯华盛顿大学医学院的科学家培训项目，他在那里研究了如何 肾盂肾炎大肠大肠杆菌侵入膀胱细胞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医院的儿科和传染病 在医院，他加入了Gautam Dantas博士的实验室，他是微生物组和抗生素方面的著名专家 阻力使用来自已建立的超过70，000份住院新生儿粪便的粪便样本， 博士Schwartz开发了一种新的婴儿微生物组发育和破坏的gnotobiotic小鼠模型。他 用新生儿粪便定殖无菌母鼠，用临床相关的 抗生素剂量。他已经确定了特定的微生物组-抗生素组合导致小鼠死亡 伴随着微生物组破坏和免疫失调。核心假设是抗生素 治疗使具有某些微生物群和耐药基因组组成的婴儿易患菌血症或 培养阴性的迟发性败血症该提案的具体目标是：1）界定早期生活的影响， 抗生素对人类婴儿微生物组成熟、肠道粘膜免疫反应和对 菌血症，和2）确定菌血症和培养阴性迟发性的微生物和免疫机制 新生儿微生物组人源化小鼠模型中的败血症。拟议的研究将利用微生物组 测序、流式细胞术、宿主免疫分析和计算建模，以确定可改变的风险因素 改善新生儿重症监护病房的抗生素处方，总体目标是降低发病率， 迟发性脓毒症的死亡率。导师，丹塔斯博士，将主要监督该项目提供培训， 微生物组分析、耐药基因组测序和生物信息学建模。施瓦茨博士已经组装了一个 咨询委员会，具有新生儿感染、抗生素治疗、肠道微生物组发育和 破坏，以及粘膜和外周免疫反应，以肠道和病原菌。培训 计划包括技术专长的成就，赠款写作技巧，负责任的研究行为， 通过一对一的学习，大学赞助的研讨会，以及在 个国际性会议华盛顿大学医学院是理想的培训环境， 广泛的跟踪记录，杰出的资源，对医生科学家的承诺，以及必要的专业知识， 完成拟议的研究。这个K 08奖将提供必要的技能和资源，博士。 施瓦茨要求成为一名成功的医生科学家，其实验室研究婴儿微生物组宿主 接口.

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.