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

项目摘要/摘要 这项提案的目标是描述一项为期五年的培训和指导计划，为德鲁·施瓦茨医学博士、 博士将成为研究抗生素对早产影响的独立内科科学家研究员 新生儿微生物群与宿主反应。施瓦茨博士获得医学博士和医学博士学位。 圣路易斯华盛顿大学医学院的科学家培训计划，在那里他学习了如何 致尿性大肠埃希菌侵入膀胱细胞，引起严重的尿路感染。在经过临床培训后 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，他是一位著名的微生物组和抗生素专家 抵抗。使用来自已建立的7万多名住院新生儿粪便储存库的粪便样本， 施瓦茨博士开发了一种新的灵知生菌小鼠模型，研究婴儿微生物组的发育和破坏。他 用新生儿粪便定植无菌母鼠，并治疗临床相关的微生物群人性化幼崽 抗生素的剂量。他已经确定了特定的微生物群-抗生素组合会导致老鼠死亡 伴随着微生物群的破坏和免疫失调。中心假设是抗生素 治疗使具有某些微生物组和耐药组成分的婴儿容易患上细菌症或 培养阴性的迟发性败血症。该提案的具体目的是：1)定义早年生活的影响 抗生素对婴儿微生物组成熟、肠道黏膜免疫反应和易感性的影响 菌血症，以及2)确定菌血症和培养阴性晚发性的微生物和免疫机制 新生儿微生物群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机建模以确定可更改的风险因素 完善新生儿重症监护病房的抗生素处方，总体目标是减少发病率和 迟发性脓毒症的死亡率。导师丹塔斯博士将主要监督提供以下培训的项目 微生物组分析、耐药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，专门从事新生儿感染、抗生素治疗、肠道微生物群开发和 破坏，粘膜和外周对共生菌和病原菌的免疫反应。培训 计划结合了技术专长的成就、拨款撰写技能、负责任的研究行为，以及 通过一对一学习、大学赞助的研讨会以及演讲和研讨会 国际会议。华盛顿大学医学院是理想的培训环境，因为 广泛的记录，出色的资源，对内科科学家的承诺，以及必要的专业知识 完成建议的研究。该K08奖项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内科科学家，他的实验室研究婴儿微生物组宿主 界面。

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.