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.
Pediatric acute respiratory distress syndrome (PARDS) is a heterogeneous syndrome characterized by severe, refractory hypoxemia not explained by heart failure or fluid overload that affects 6% of children requiring invasive mechanical ventilation in the pediatric intensive care unit (PICU). More than 40% of children who die PARDS-related deaths are previously healthy, very young children and there are currently no targeted therapies to treat PARDS apart from supportive care. The goal of this project is to identify molecular pathways that contribute to prolonged acute hypoxemic respiratory failure to guide the development of personalized therapies to alleviate the sequelae of lung injury and reduce long-term morbidity and mortality of critically ill children with acute lung injury.
