Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. The syndrome affects 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 30%. Infection is the leading cause of pediatric ARDS, with up to 80% of cases occurring in the setting of either infectious pneumonia or non-pulmonary sepsis. There are no specific pharmacological therapies for ARDS despite several trials, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are typically extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Recent evidence has implicated nucleosomes, the DNA/histone complexes released into circulation as a result of nuclear chromatin degradation after cellular damage, as pathogenic in systemic sepsis and trauma-associated ARDS in adults. Normally located within the nucleus, nucleosomes released into the circulation are toxic to multiple cell types, offering a novel mechanism linking diverse inciting insults with subsequent lung injury. However, whether nucleosomes are pathogenic in pediatric ARDS is unknown. The broad objectives of this proposal are to 1) determine the association between nucleosome levels and outcomes in a cohort of pediatric ARDS; 2) determine the composition of the pathogenic nucleosomes by identifying specific histones and associated post-translational modifications; 3) demonstrate the pathogenicity of post-translationally modified and unmodified histones in in vitro cell culture and in vivo rodent models; and 4) develop the skills necessary to become a successful translational scientist in pediatric lung injury by focused training in epidemiology and proteomics. The proposed studies leverage existing infrastructure at the Children?s Hospital of Philadelphia and University of Pennsylvania to conduct a cohort study in pediatric ARDS and to perform novel proteomic analyses. A diverse and experienced mentorship team, with expertise in basic, translational, and clinical research, has been assembled to provide guidance through a rigorous training plan involving research conduct, didactics in advanced epidemiological analyses and proteomics, and intensive mentorship. The proposed studies will establish the relevance of plasma nucleosomes in pediatric ARDS, provide a novel technique for isolating and analyzing nucleosome-associated proteins, and improve our understanding of the pathogenicity of circulating histones. We will use these insights to study novel therapies for ARDS, and I will gain the necessary training in clinical research and proteomics to mature into an independent translational scientist working to improve outcomes for critically ill children.
Acute respiratory distress syndrome (ARDS) is common and deadly in children, and studies focused on the pathogenic mechanisms specifically in pediatrics are lacking. Nucleosomes, the DNA/histone complexes released into circulation as a result of nuclear chromatin degradation after cellular damage, are toxic to multiple cell types, offering a novel mechanism linking diverse inciting insults with subsequent lung injury. The goal of this research is to determine the relevance of nucleosomes in pediatric ARDS, and to characterize the pathogenic histones and their associated post-translational modifications, thereby providing a potential therapeutic target for ARDS treatment.
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