PROJECT SUMMARY / ABSTRACT Almost 2 million Americans are hospitalized with sepsis each year, and nearly one in five don’t survive. Most efforts to reduce sepsis deaths begin with the premise that patients are largely similar, and that targeting therapeutics to a single mechanism will improve outcomes. But sepsis patients differ in pathogen, biology, outcomes, and are proposed to have treatment responsive endotypes. Greater study of sepsis endotypes has been limited by costly infrastructure and biospecimen collection that is not scalable. To solve this challenge, we will use a clinical remnant biorepository to understand feasibility, integrity, and scientific value for mechanistic sepsis research. We will evaluate traditional biomarkers, quantitative proteomics, metabolomics, lipidomics, and pathogen genomic sequencing in remnant specimens and graduate successful data “layers” to a scaled, community hospital repository. This cross-cutting project will be supervised by an external advisory board with expertise in inflammation, immunology, computational and systems biology, and laboratory and pathology medicine. This approach will further develop our NIGMS-funded clinical-translational laboratory, creating new hypotheses from a diverse, academic and community hospital remnant biorepository acquired from an endotype-enriched population of sepsis patients. Finally, we will further integrate these data with multi-omics read-outs in severely injured trauma patients to explore shared/unshared mechanisms in critical illness.