Nasopharyngeal Microbiome and Risk of Bacterial Pathogen Colonization in Infants

摘要 这项以患者为导向的导师研究职业发展奖提案将提供一个极好的 教育环境、专家指导以及说教和实践培训，以促进马修·凯利博士的 发展成为一名独立的调查员。凯利博士的长期职业目标是开发使用 有针对性地操纵微生物群以预防和治疗儿童感染。拟议的研究， 博茨瓦纳的母婴配对参与，将提供对鼻咽潜在影响的洞察 微生物群对儿童肺炎风险的影响。肺炎是全球儿童的头号传染病杀手， 每年造成92万人死亡。其中一半以上的死亡发生在撒哈拉以南非洲地区。 鼻咽部定植先于细菌病原体引起的肺炎，鼻咽部 微生物群可能是这些细菌侵袭下呼吸道和定植的屏障。 在这项提案中，凯利博士将使用肺炎链球菌作为模型，以进一步了解这种动态 鼻咽微生物群与呼吸道细菌病原体的相互作用。他还将发展 应用传统多变量统计进行纵向分析的系统方法 微生物组数据。候选人是传染病系儿科助理教授，网址为 杜克大学。他之前是大卫·N·平卡斯全球健康联谊会的非洲研究员 费城儿童医院，并一直在博茨瓦纳进行临床研究 2012年。凯利博士对K23项目的短期目标是：1)获得生物信息学和计算生物学 分析微生物组测序数据的技能；2)在设计和实施 儿童的前瞻性临床研究；以及3)开发使用常规多变量统计的模型 方法对纵向微生物组数据进行分析。凯利博士的指导团队在 微生物组、生物信息学、传统多变量统计学和全球健康研究，以及 成功地指导初级教员。凯利博士的主要导师罗尔斯博士领导了一项由美国国立卫生研究院资助的研究 研究微生物组和宿主-微生物相互作用的计划。他的联合导师坎宁安博士和 在进行国际临床研究和开发新的统计学方面具有专业知识 传染病研究的方法学。他的外部顾问斯蒂恩霍夫博士拥有的不仅仅是 在博茨瓦纳有10年的临床研究经验，将协助研究实施。剩下的 凯利博士的外部咨询委员会成员是早期婴儿微生物组(SEED)和 儿科肺炎(沙阿)。拟议的研究可能最终导致第一个合理的- 设计了预防肺炎和其他呼吸道感染的益生菌。在完成 职业发展和研究计划，凯利博士将拥有必要的技能来领导使用 有针对性地操纵微生物群以预防和治疗儿童感染。

ABSTRACT This Mentored Patient-Oriented Research Career Development Award proposal will provide an excellent educational environment, expert mentorship, and didactic and practical training to facilitate Dr. Matthew Kelly’s development as an independent investigator. Dr. Kelly’s long-term career goal is to develop strategies that use targeted manipulation of the microbiome to prevent and treat infections in children. The proposed research, involving mother-infant pairs in Botswana, will provide insight into the potential impact of the nasopharyngeal microbiome on the risk of childhood pneumonia. Pneumonia is the leading infectious killer of children globally, accounting for 920,000 deaths each year. More than half of these deaths occur in sub-Saharan Africa. Colonization of the nasopharynx precedes pneumonia caused by bacterial pathogens, and the nasopharyngeal microbiome may serve as a barrier to colonization and invasion of the lower respiratory tract by these bacteria. In this proposal, Dr. Kelly will use Streptococcus pneumoniae as a model to further knowledge of the dynamic interactions between the nasopharyngeal microbiome and bacterial respiratory pathogens. He will also develop a systematic approach for the application of conventional multivariable statistics to the analysis of longitudinal microbiome data. The candidate is an Assistant Professor of Pediatrics in the Division of Infectious Diseases at Duke University. He was previously the Africa Fellow in the David N. Pincus Global Health Fellowship through the Children’s Hospital of Philadelphia, and has been conducting clinical research studies in Botswana since 2012. Dr. Kelly’s short-term goals for the K23 program are: 1) acquire bioinformatics and computational biology skills for the analysis of microbiome sequencing data; 2) obtain additional expertise in the design and conduct of prospective clinical studies in children; and 3) develop a model for use of conventional multivariable statistical methods in analyses of longitudinal microbiome data. Dr. Kelly’s mentorship team has expertise in the microbiome, bioinformatics, conventional multivariable statistics, and global health research, and a history of successful mentorship of junior faculty. Dr. Kelly’s primary mentor, Dr. Rawls, leads an NIH-funded research program studying the microbiome and host-microbe interactions. His co-mentors, Drs. Cunningham and Hudgens, have expertise in the conduct of international clinical research and the development of novel statistical methodologies for studies of infectious diseases, respectively. His external advisor, Dr. Steenhoff, has more than 10 years of clinical research experience in Botswana and will assist with study implementation. The remaining members of Dr. Kelly’s external advisory committee are experts in the early infant microbiome (Seed) and pediatric pneumonia (Shah). The proposed research could ultimately lead to development of the first rationally- designed probiotics for the prevention of pneumonia and other respiratory infections. Upon completion of the career development and research plans, Dr. Kelly will have the necessary skillset to lead clinical studies that use targeted manipulation of the microbiome for the prevention and treatment of infections in children.