Airway Immune Response in Critically Ill Children-Precision Medicine in Children At Risk for Acute Respiratory Distress Syndrome

项目总结 大多数儿童急性呼吸窘迫综合征(PARDS)是由下呼吸道触发的 感染，40%以上死于扑克牌的儿童以前很健康，很小 孩子们。每个孩子独特的呼吸道环境导致了Pards的异质性，而这 由于缺乏对呼吸道环境如何影响免疫的洞察，导致没有加速的治疗方法 从帕兹恢复过来。 该提案描述了Jocelyn Grunwell博士将获得的五年职业发展和研究计划 1)高级生物统计学和大数据管理方面的培训和专业知识，2)临床试验的合理设计， 以及3)对急性下呼吸道引发的PARDS产生新的生物学和机械学见解 肠道感染。这项K23提案的最终目标是成为一名独立资助的医生- 科学家专注于为患有急性肺损伤的危重儿童开发精确的治疗方法。使用 在临床研究方法和先进的生物统计学方法方面的额外培训，这项K23奖将 探讨PARDS和LINK发生和发展的新的病理生物学机制 这些生物内型具有临床表型，以达到以下目的：1)确定其表型 中性粒细胞和对二次损伤的反应，2)决定是否有重新招募的气道 中性粒细胞通过精氨酸耗竭机制抑制T细胞功能，以及3)决定 内型-表型群使用潜伏级分析预测临床结果。 研究异质生物机制并将其与临床PARDS表型联系起来将是 在安妮·菲茨帕特里克博士领导的知识渊博和经验丰富的指导团队的帮助下。菲茨帕特里克博士是一位 生物统计学方法在异质性儿科疾病表型鉴定方面的专家，例如 哮喘和代谢和基因表达导致的高维患者数据的分析 学习。导师团队得到了Adrienne Randolph医生的赞扬，他是一名儿科强化医生，患有 对流感引起的肺损伤、呼吸道细胞因子环境和功能的复杂分析感兴趣 用病毒和细菌模拟物分析对刺激的先天免疫反应。导师团队和 机构环境是促进与儿科急症相关的职业发展和合作的理想环境 危重病的肺损伤和后遗症。 格伦威尔博士在分子方法方面拥有出色的基础，获得了博士学位和达蒙博士学位。 Runyon获得加州大学伯克利分校和旧金山大学生物化学博士后奖学金， 分别进行了分析。在K23完成后，Grunwell博士将成为鉴定内型-表型的专家 使用先进的生物统计学方法对复杂危重病综合征进行关联，然后谁将使用HER 分子训练，以磨练新的生物机制，为危重儿童带来精确的药物。

PROJECT SUMMARY The majority of pediatric acute respiratory distress syndrome (PARDS) is triggered by lower respiratory tract infections, and more that 40% of children who die PARDS-related deaths are previously healthy, very young children. The unique airway environment of each child contributes to the heterogeneity of PARDS, and this lack of insight into how the airway environment influences immunity has resulted in no therapies that hasten recovery from PARDS. This proposal describes a five-year career development and research plan for Dr. Jocelyn Grunwell to gain training and expertise in 1) advanced biostatistics and big data management, 2) sound design of clinical trials, and 3) to generate new biological and mechanistic insights into PARDS triggered by acute lower respiratory tract infections. The ultimate objective of this K23 proposal is to become an independently funded physician- scientist focused on developing precision therapies for critically ill children with acute lung injury. With additional training in clinical research methodology and advanced biostatistical methods, this K23 award will investigate novel pathobiological mechanisms of importance to the onset and progression of PARDS and link these biologic endotypes with clinical phenotypes to achieve the following aims: 1) determine the phenotype of recruited airway neutrophils and response to secondary insult, 2) determine whether recruited airway neutrophils suppress T cell function through an arginine depletion mechanism, and 3) determine whether endotype-phenotype clusters predict clinical outcomes using latent class analysis. Investigating heterogeneous biological mechanisms and linking them to clinical PARDS phenotypes will be aided by a knowledgeable and experienced mentorship team led by Dr. Anne Fitzpatrick. Dr. Fitzpatrick is an expert in biostatistical approaches to phenotype identification in heterogeneous pediatric disorders such as asthma and in the analysis of high-dimensional patient data resulting from metabolomic and gene expression studies. The mentorship team is complimented by Dr. Adrienne Randolph, a pediatric intensivist with an interest in influenza induced lung injury, complex analyses of the airway cytokine environment, and functional assays of the innate immune response to stimulus by viral and bacterial mimetics. The mentorship team and institutional environment are ideal to foster career development and collaboration related to pediatric acute lung injury and sequelae of critical illness. Dr. Grunwell has had outstanding foundation in molecular methods, having earned a PhD and a Damon- Runyon Postdoctoral fellowship in biochemistry from the University of California, Berkeley and San Francisco, respectively. At the completion of this K23, Dr. Grunwell will be an expert in identifying endotype-phenotype associations of complex critical illness syndromes using advanced biostatistical methods who will then use her molecular training to hone in on novel biological mechanisms to bring precision medicine to critically ill children.