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

危重儿童的气道免疫反应——急性呼吸窘迫综合征风险儿童的精准医疗

基本信息

批准号：
10597605
负责人：
Jocelyn Rebecca Grunwell
金额：
$ 17.32万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597605
关键词：
Acute Acute Lung Injury Acute Respiratory Distress Syndrome Acute respiratory failure Affect Apoptosis Arginine Asthma Bacteria Bacterial Pneumonia Behavior Biochemistry Biological Biological Assay Biometry Biostatistical Methods California Categories Cell physiology Cells Cessation of life Child Childhood Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Complex Complex Analysis Critical Illness Critically ill children Cytoplasmic Granules Data Development Development Plans Disease Doctor of Philosophy Endothelium Environment Epithelium Exocytosis Exposure to Fellowship Fluid overload Fostering Foundations Functional disorder Funding Gene Expression Goals Heart failure Heterogeneity Hypoxemia Hypoxemic Respiratory Failure Immune Immune checkpoint inhibitor Immunity Impairment Influenza Innate Immune Response Institution Interferons Intubation Link Liquid substance Lower Respiratory Tract Infection Macrophage Mechanical ventilation Mentored Clinical Scientist Development Program Mentored Patient-Oriented Research Career Development Award Mentorship Methods Modeling Molecular Morbidity - disease rate NADPH Oxidase Pathway interactions Patients Pediatric Acute Lung Injury Pediatric Acute Respiratory Distress Syndrome Pediatric Intensive Care Units Pharmacotherapy Phenotype Physicians Play Postdoctoral Fellow Pre-Clinical Model Precision therapeutics Pulmonary Edema Recovery Refractory Research Research Design Research Methodology Resolution Respiratory Burst Respiratory Tract Infections Risk San Francisco Scientist Secondary to Stimulus Supportive care Syndrome T-Cell Proliferation T-Lymphocyte Testing Training Translational Research United States National Institutes of Health Universities Viral Viral Pneumonia acute hypoxemic respiratory failure airway immune response arginase big data management career development clinical phenotype co-infection cytokine experience functional status high dimensionality insight interest lung injury metabolomics mimetics mortality neutrophil novel personalized care personalized medicine precision medicine predict clinical outcome primary outcome recruit research and development response secondary outcome sound targeted treatment

项目摘要

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.

项目摘要小儿急性呼吸窘迫综合征（PARDS）多由下呼吸道感染引起感染，超过40%死于PARDS相关死亡的儿童以前是健康的，孩子每个儿童独特的气道环境导致PARDS的异质性，由于缺乏对气道环境如何影响免疫力的了解，从PARDS中恢复。该提案描述了一个为期五年的职业发展和研究计划博士乔斯林格伦威尔获得 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，和3）对急性下呼吸道疾病引发的PARDS产生新的生物学和机制见解肠道感染。这个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疗法。与在临床研究方法和先进的生物统计方法的额外培训，这个K23奖将研究PARDS发病和进展的新病理生物学机制，将这些生物学内型与临床表型进行比较，以实现以下目的：1）确定募集的气道中性粒细胞和对二次损伤的反应，2）确定是否募集了气道中性粒细胞，中性粒细胞通过精氨酸耗尽机制抑制T细胞功能，以及3）确定是否内型-表型聚类使用潜在类别分析预测临床结果。研究异质性生物学机制并将其与临床PARDS表型联系起来，由安妮菲茨帕特里克博士领导的知识渊博、经验丰富的导师团队提供帮助。菲茨帕特里克医生是专家在生物统计方法，以表型鉴定异质性儿科疾病，如哮喘和分析由代谢组学和基因表达产生的高维患者数据问题研究导师团队由儿科重症监护医师Adrienne兰多夫博士称赞，流感引起的肺损伤，气道细胞因子环境的复杂分析，以及功能性对病毒和细菌模拟物刺激的先天免疫应答的测定。导师团队和机构环境是促进与儿科急性肺损伤和危重病后遗症。博士Grunwell在分子方法方面有着出色的基础，他获得了博士学位和Damon- Runyon获得加州大学伯克利分校和旧金山弗朗西斯科分校生物化学博士后奖学金，分别完成K23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研究复杂的危重病综合征的关联，分子训练，磨练新的生物机制，为重症儿童提供精准医疗。