Clinical and host microbiome features in the development of acute otitis media

摘要 这项导师职业发展(K01)奖的建议将提供一个出色的教育环境， 为Jillian Hurst博士提供指导和培训，她是一名儿科传染病研究员，其主要职业生涯 目标是整合临床和生物学数据，以加深我们对微生物组和 改变儿童常见感染易感性的相关宿主因素赫斯特博士最初接受过 生物化学和分子生物学，在过去的五年里一直从事转化型儿科研究。 这项职业发展奖将允许她接受组学和高级统计分析方面的培训，使用 大型数据集，使她能够领导使用大型临床和组学数据集的多学科团队 评估儿科常见感染的潜在因素。拟进行的研究主要集中在 上呼吸道微生物群与急性中耳炎(AOM；中耳)的发生和复发 感染)，这是儿童最常见的传染病。赫斯特博士将检验早期生命的假说 抗生素暴露扰乱了URT微生物群的发育，使儿童容易患上AOM和其他 常见的呼吸道感染。她将使用超过八年的电子健康记录数据，银行 从出生到2岁的儿童收集的纵向上呼吸道样本，以及来自 复发性AOM儿童的预期队列以实现以下特定目标：1)评估 早期接触抗生素对反复发生的AOM的影响；2)描述早期生活的影响 抗生素暴露对城市轨道交通微生物群发育的影响；以及3)评估抗生素与 复发AOM儿童的暴露和URT微生物群。这些研究的结果将指导 制定预防和治疗急性呼吸道感染及相关感染的新战略，包括指导 抗生素的使用和在城市轨道交通微生物组内可用于 恢复城市轨道交通微生物群功能，改善幼儿的呼吸健康。导师关系将会是 由三名具有互补专业知识的资深调查人员提供：克里斯托弗·伍兹博士， 传染病内科医生和临床流行病学家，擅长评估宿主对 感染剂；马修·凯利博士，儿科传染病内科医生，擅长人类 微生物组和临床组学分析；以及本杰明·戈尔茨坦博士，一位在使用方面具有专业知识的生物统计学家 用于人口健康分析的电子健康记录数据。此外，赫斯特博士将由内科提供建议 和拥有抗菌药物管理、儿科耳鼻喉科、健康信息学专业知识的外部顾问 和组学分析，以及AOM的治疗和病理生理学。完成拟议的培训和 研究活动将使赫斯特博士成为一名独立的研究员，他将领导一项由NIH资助的研究 调查儿童常见感染的宿主因素和暴露情况的计划。

ABSTRACT This Mentored Career Development (K01) Award proposal will provide an outstanding educational environment, mentoring, and training for Dr. Jillian Hurst, a pediatric infectious diseases researcher whose overarching career goal is to integrate clinical and biological data to further our understanding of the role of the microbiome and related host factors in modifying susceptibility to common childhood infections Dr. Hurst originally trained in biochemistry and molecular biology and has worked in translational pediatric research for the past five years. This career development award will allow her to receive training in omics and advanced statistical analyses using large datasets, permitting her to lead multidisciplinary teams that use large clinical and omics datasets to evaluate factors underlying common pediatric infections. The proposed research studies center on the role of the upper respiratory microbiome in the development and recurrence of acute otitis media (AOM; middle ear infection), the most common infectious disease of childhood. Dr. Hurst will test the hypothesis that early life antibiotic exposures disrupt the development of the URT microbiome, predisposing children to AOM and other common respiratory infections. She will use over eight years of electronic health records data, banked longitudinal upper respiratory specimens collected from children from birth to age 2, and samples and data from a prospective cohort of children with recurrent AOM to accomplish the following specific aims: 1) Assess the impact of early life antibiotic exposures on recurrent AOM development.; 2) Delineate the effects of early life antibiotic exposures on URT microbiome development; and 3) Evaluate associations between antibiotic exposures and the URT microbiome in children with recurrent AOM. Findings from these studies will guide the development of new strategies to prevent and treat AOM and associated infections, including guidance for antibiotic use and identification of therapeutic targets within the URT microbiome that could be leveraged to restore URT microbiome function and improve respiratory health among young children. Mentorship will be provided by a group of three established investigators with complementary expertise: Dr. Christopher Woods, an infectious diseases physician and clinical epidemiologist with expertise in the evaluation of host responses to infectious agents; Dr. Matthew Kelly, a pediatric infectious diseases physician with expertise in the human microbiome and clinical omics analyses; and Dr. Benjamin Goldstein, a biostatistician with expertise in the use of electronic health records data for population health analyses. Additionally, Dr. Hurst will be advised by internal and external advisors with expertise in antimicrobial stewardship, pediatric otolaryngology, health informatics and omics analyses, and the treatment and pathophysiology of AOM. Completion of the proposed training and research activities will establish Dr. Hurst as an independent investigator who will lead an NIH-funded research program investigating host factors and exposures underlying common infections in children.