Nasopharyngeal Microbiome and Risk of Bacterial Pathogen Colonization in Infants

摘要 这个指导以病人为导向的研究职业发展奖的建议将提供一个很好的 教育环境，专家指导，教学和实践培训，以促进马修凯利博士的 发展成为独立调查员。凯利博士的长期职业目标是制定战略， 有针对性地操纵微生物组，以预防和治疗儿童感染。拟议的研究， 涉及博茨瓦纳的母婴对，将深入了解鼻咽炎的潜在影响， 微生物组对儿童肺炎风险的影响。肺炎是全球儿童的主要传染性杀手， 导致每年92万人死亡其中一半以上的死亡发生在撒哈拉以南非洲。 鼻咽部的定植先于细菌病原体引起的肺炎，并且鼻咽部 微生物组可作为这些细菌定植和侵入下呼吸道的屏障。 在这项建议中，凯利博士将使用肺炎链球菌作为模型，以进一步了解动态 鼻咽微生物组和细菌性呼吸道病原体之间的相互作用。他还将开发 应用常规多变量统计分析纵向 微生物组数据。该候选人是一个儿科助理教授在传染病科， 杜克大学。他以前是大卫N的非洲研究员。平卡斯全球健康奖学金通过 费城儿童医院，并一直在博茨瓦纳进行临床研究， 2012.凯利博士的K23计划的短期目标是：1）获得生物信息学和计算生物学 微生物组测序数据分析的技能; 2）获得设计和执行的额外专业知识 在儿童中的前瞻性临床研究;和3）开发一个模型，用于使用传统的多变量统计 纵向微生物组数据分析方法。凯利博士的导师团队在以下方面拥有专业知识： 微生物组，生物信息学，传统的多变量统计，全球健康研究，以及 初级教师的成功指导。凯利博士的主要导师罗尔斯博士领导了一项由NIH资助的研究， 研究微生物组和宿主微生物相互作用的项目。他的共同导师坎宁安博士和 Hudgens，在国际临床研究和新的统计学发展方面具有专业知识， 研究传染病的方法。他的外部顾问Steenhoff博士 在博茨瓦纳有10年的临床研究经验，将协助研究实施。其余 凯利博士的外部咨询委员会成员是早期婴儿微生物组（种子）的专家， 小儿肺炎（Shah）。拟议中的研究可能最终导致第一个合理的发展- 专为预防肺炎和其他呼吸道感染而设计的益生菌。完成后 职业发展和研究计划，凯利博士将有必要的技能，以领导临床研究，使用 有针对性地操纵微生物组，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.