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：
10390300
负责人：
Jocelyn Rebecca Grunwell
金额：
$ 18.95万
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/10390300
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 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 Epithelial 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 Interferons Link Liquid substance Lower Respiratory Tract Infection Mechanical ventilation 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 Pre-Clinical Model Precision therapeutics Pulmonary Edema Recovery Refractory Research Research Design Research Methodology Resolution Respiratory Burst Respiratory Tract Infections Risk SECTM1 gene 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 macrophage 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.

项目概要大多数小儿急性呼吸窘迫综合征 (PARDS) 是由下呼吸道引发的感染，超过 40% 死于 PARDS 相关死亡的儿童以前都很健康，而且非常年幼孩子们。每个儿童独特的气道环境导致了 PARDS 的异质性，这由于缺乏对气道环境如何影响免疫力的深入了解，导致没有任何治疗方法可以加速从 PARDS 中恢复。该提案描述了 Jocelyn Grunwell 博士的五年职业发展和研究计划，以获得 1) 先进的生物统计学和大数据管理，2) 完善的临床试验设计的培训和专业知识， 3) 对急性下呼吸道引发的 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准疗法。和临床研究方法和先进生物统计方法方面的额外培训，该 K23 奖项将研究对 PARDS 的发生和进展具有重要意义的新病理生物学机制及其联系这些具有临床表型的生物内型可以达到以下目的：1）确定表型气道中性粒细胞募集和对继发性损伤的反应，2) 确定气道是否募集中性粒细胞通过精氨酸耗竭机制抑制 T 细胞功能，并且 3) 确定是否内型-表型簇使用潜在类别分析预测临床结果。研究异质生物学机制并将其与临床 PARDS 表型联系起来由 Anne Fitzpatrick 博士领导的知识渊博、经验丰富的导师团队提供帮助。菲茨帕特里克博士是异质儿科疾病表型鉴定的生物统计方法专家，例如哮喘以及代谢组学和基因表达产生的高维患者数据分析研究。指导团队得到了儿科重症监护医师 Adrienne Randolph 博士的称赞。对流感引起的肺损伤、气道细胞因子环境的复杂分析以及功能性的兴趣对病毒和细菌模拟物刺激的先天免疫反应的测定。导师团队和机构环境非常适合促进儿科急症相关的职业发展和合作肺损伤和危重疾病后遗症。 Grunwell 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- 加州大学伯克利分校和旧金山分校的鲁尼恩生物化学博士后奖学金，分别。完成本 K23 课程后，Grunwell 博士将成为识别内型-表型的专家使用先进的生物统计学方法研究复杂危重疾病综合征的关联，然后他们将使用她分子训练旨在研究新的生物机制，为危重儿童带来精准医疗。