Understanding longitudinal microbiome change in relation to immunologic outcomes in pediatric SCT recipients.

项目总结/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教学和 体验式培训，专家指导，和一个特殊的研究环境，以促进博士凯特琳 Elgarten作为独立临床科学家的发展。Elgarten博士的长期职业目标是开发 使用微生物组的目标测量和操纵来预测和预防不良反应的策略 儿科干细胞移植（SCT）的结果。尽管SCT提供了治愈1500多名患者的机会， 儿童每年与危及生命的疾病的血液和免疫系统，成功的， 治疗受到新免疫系统的异常和/或延迟恢复的限制 疾病（GVHD），严重感染和生存率下降。在本提案中，Elgarten博士将利用来自 三个儿科队列，以表征在治疗期间发生的胃肠道微生物组的破坏， SCT。她将定义与急性GVHD和外周免疫细胞相关的微生物组特征。 恢复，并确定临床相关微生物组破坏的药理学驱动因素。通过 适应非线性混合效应模型的重复测量，以模拟多维和高度 微生物组的动态性质，这项研究将提供一个更好的理解的因果关系， SCT后的微生物组和免疫事件。从而为小说的鉴定奠定基础 生物标志物和干预措施的合理设计，以改善SCT的结果。这些目标的实现还将 为候选人提供进行观察性微生物组研究的基本经验， 在先进的生物信息学和必要的统计方法，以研究的相互作用的关键培训， 微生物组、药理学暴露和临床因素定义了SCT后不良结局的风险。 候选人是一名儿科肿瘤学家和SCT医生，接受过药物流行病学的正式培训， 具有SCT支持性治疗临床研究背景。她渴望把她的观点作为一个 临床医生和流行病学家在这种复杂的临床情况下研究纵向微生物组变化。博士 Elgarten的K23计划的目标是：1）进行以患者为导向的研究项目，将产生临床 有意义的结果，2）获得微生物组测序数据分析的生物信息学技能，以及3） 基于非线性混合效应模型开发SCT中纵向微生物组数据分析平台 重复的措施。她组建了一个强大的导师和咨询团队，由Brian Fisher博士领导， 包括微生物组-宿主生物学、深度测序方法和生物信息学方面的国家专家， 基于定量模型的方法和转化流行病学。这一指导，结合广泛的 费城儿童医院和宾夕法尼亚大学的现有资源将确保 完成了拟议的研究和培训目标，以及Elgarten博士成功过渡到 独立调查员

PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development Award proposal will provide didactic and experiential training, expert mentorship, and an exceptional research environment to facilitate Dr. Caitlin Elgarten's development as an independent clinician scientist. Dr. Elgarten's long-term career goal is to develop strategies that use targeted measurement and manipulation of the microbiome to predict and prevent adverse outcomes of pediatric stem cell transplant (SCT). Although SCT offers a chance for cure for more than 1,500 children each year with life-threatening disorders of the hematologic and immune systems, the success of this treatment is limited by aberrant and/or delayed recovery of the new immune system leading to graft-versus-host disease (GVHD), serious infection and reduced survival. In this proposal, Dr. Elgarten will leverage data from three pediatric cohorts to characterize the disruption of the gastrointestinal tract microbiome that occurs during SCT. She will define the microbiome features that associate with acute GVHD and peripheral immune cell recovery, and identify the pharmacologic drivers of clinically relevant microbiome disruption. Through the adaptation of non-linear mixed effects models for repeated measures to model the multidimensional and highly dynamic nature of the microbiome, this study will deliver a greater understanding of the causal association of the microbiome and immune events after SCT. In doing so, this work will lay the foundation for identification of novel biomarkers and the rational design of interventions to improve SCT outcomes. Execution of these aims will also provide the candidate with essential experience in conducting observational microbiome research and with critical training in the advanced bioinformatics and statistical methods necessary to study the interaction of the microbiome, pharmacologic exposures and clinical factors that define risk for adverse outcomes after SCT. The candidate is a pediatric oncologist and SCT physician with formal training in pharmacoepidemiology and a background in clinical research focused on supportive care in SCT. She aspires to bring her perspective as a clinician and epidemiologist to the study of longitudinal microbiome change in this complex clinical scenario. Dr. Elgarten's goals for the K23 program are: 1) conduct a patient-oriented research project that will yield clinically meaningful results, 2) acquire bioinformatics skills for the analysis of microbiome sequencing data, and 3) develop a platform for analysis of longitudinal microbiome data in SCT based on non-linear mixed effects models for repeated measures. She has assembled a strong mentorship and advisory team, led by Dr. Brian Fisher, and inclusive of national experts in microbiome-host biology, deep sequencing methods and bioinformatics, quantitative model-based methods, and translational epidemiology. This guidance, combined with the extensive resources available at the Children's Hospital of Philadelphia and the University of Pennsylvania, will ensure the accomplishment of the proposed research and training goals and Dr. Elgarten's successful transition to independent investigator.