The contribution of antibiotic exposure in the prenatal, peripartum and infancy period to intestinal microbiome perturbations and association with early childhood obesity.

本文提出的研究计划是支持医学博士Suchitra Hourigan发展成为一个 独立研究员，旨在对肠道微生物组的作用进行新颖和变革性的研究 儿童早期健康和疾病的发展，重点是肥胖症。她寻求K23奖，以 获得对她的过渡至关重要的技能，知识，正规培训和指导研究经验 从一个早期的职业医生，科学家在试验设计，招募， 流行病学和微生物组分析提供给独立科学家， 对导致儿童疾病的微生物群落的影响。两个重要的组成部分，她的过渡到 研究独立性是在1）试验的进行和设计以及翻译 微生物组研究和2）纵向微生物组分析结合丰富的 流行病学数据。拟议的K23职业发展计划将实现这些目标。 肥胖是一种世界性的流行病。在生命的早期有一个关键的窗口期， 部分原因是肠道微生物组和代谢程序的建立， 发生.流行病学研究表明，早期接触抗生素会增加儿童患病的风险。 肥胖假设早期抗生素暴露导致有害的肠道微生物群扰动， 将宿主“编程”为易肥胖的代谢表型，这种表型在抗生素停药后仍然存在; 然而，这从未在人类中显示。为了验证这一假设，前瞻性纵向研究， 需要进行微生物分析。本项目的总体目标是确定以下方面的相对贡献： 产前、围产期和婴儿期抗生素暴露于肠道微生物组扰动， 与幼儿肥胖有关。这将通过利用独特的 在Inova建立的纵向队列研究（NIH-NICHD ECHO 4UH 3 OD 023337 -03）。 博士Hourigan将在Inova转化医学丰富的研究环境中开展这项提案 她在约翰霍普金斯医学院接受额外的培训，并在那里继续担任教职。 在她的主要导师John Niederhuber博士（执行董事）的合作和支持指导下， Inova健康系统副总裁兼基因组学和生物信息学研究所首席执行官， Inova），共同导师Cynthia Sears博士，医学博士（传染病科医学教授， 胃肠病学，约翰霍普金斯）和顾问，她很好地定位完成拟议的活动。在 除了领导这项研究，Hourigan博士还将参加课程，研讨会，科学会议， 参加每周的学习活动与她的导师。这种指导性培训将使Hourigan博士能够成长 成为一名独立的研究人员，在纵向微生物组的设计，实施和分析方面具有专业知识 研究，重点是了解发育中的肠道微生物组在儿童健康结果中的作用。

The research program proposed herein is to support the development of Suchitra Hourigan, MD, into an independent investigator aiming to conduct novel and transformative research into the role of gut microbiome development in early childhood health and disease, with a focus on obesity. She seeks a K23 award in order to obtain the skill set, knowledge, formalized training and mentored research experience critical for her transition from an early career physician-scientist with a solid foundation in the basics of trial design, recruitment, epidemiology and microbiome analysis to an independent scientist who conducts trials designed to intervene on microbial communities that contribute to childhood disease. Two essential components of her transition into research independence are hands-on mentored training in 1) the conduct and design of trials and translational microbiome studies and 2) the interpretation of longitudinal microbiome analysis combined with rich epidemiological data. The proposed K23 Career Development plan will accomplish these goals. Obesity is a worldwide epidemic. There is a critical window in very early life that is conjectured to be predictive of later obesity risk, in part due to the establishment of the gut microbiome and metabolic programming that occur. Epidemiological studies have indicated that early exposure to antibiotics increases the risk of childhood obesity. It is hypothesized that early antibiotic exposure causes detrimental gut microbiota perturbations that ‘program’ the host to an obesity-prone metabolic phenotype which persists after discontinuation of antibiotics; however this has never been shown in humans. To test this hypothesis, prospective longitudinal studies with microbiome analysis are needed. The overall goal of this project is to determine the relative contributions of antibiotic exposure in the prenatal, peripartum and infancy period to intestinal microbiome perturbations and association with early childhood obesity. This will be achieved by leveraging the infrastructure of the unique established longitudinal cohort study at Inova (NIH-NICHD ECHO 4UH3OD023337-03). Dr. Hourigan will carry out this proposal in the rich research environment of the Inova Translational Medicine Institute with additional training at the Johns Hopkins School of Medicine where she remains a faculty member. Under the collaborative and supportive mentorship of her primary mentor Dr. John Niederhuber, MD (Executive Vice President of the Inova Health System and CEO of the Genomics and Bioinformatics Research Institute at Inova), co-mentor Dr. Cynthia Sears, MD (Professor of Medicine in the Division of Infectious Disease and Gastroenterology, Johns Hopkins) and advisors, she is well positioned to complete the proposed activities. In addition to leading this research, Dr. Hourigan will attend courses, workshops, scientific meetings and participate in weekly study activities with her mentors. This mentored training will enable Dr. Hourigan to grow into an independent researcher, with expertise in the design, conduct and analysis of longitudinal microbiome studies, focused on understanding role of the developing gut microbiome in childhood health outcomes.