Sepsis syndrome consists of a dysregulated host response to infection involving a complex interplay between proinflammatory and anti-inflammatory processes. Initially, sepsis is characterized by excessive cytokine release that shifts over time to a state of immune exhaustion characterized by T cell dysfunction and apoptosis. Although most sepsis-related deaths occur during this late hypoimmune state, there are currently no reliable biomarkers to stratify immune status of patients with sepsis to guide precision delivery of immunotherapeutic agents. Exosomes are membrane-bound nanovesicles containing miRNAs which are increasingly recognized as key regulators of host immune response. Leveraging recent advances in microfluidic detection of exosomes and associated cargo, the goal of this proposal is to accurately define key immune pathways disrupted in sepsis and to identify clinically useful biomarkers of immune status. Previous research has largely focused on the role of exosomes in mediating inflammation and endothelial dysfunction characteristic of septic shock; however, preliminary data from our laboratory challenge this paradigm and demonstrate that circulating exosomes also contribute to sepsis-induced immune suppression. Based on this premise, we hypothesize that sepsis results in immune dysfunction with corresponding changes in circulating concentrations of exosomal miRNA (exo-miRNA) that can be used as biomarkers of immune status. To test these hypotheses, we will execute the following Specific Aims: i) identify circulating exo-miRNA markers of sepsis; ii) evaluate the effect of plasma-derived exosomes from septic patients on immune function; and iii) develop a nanoengineered chip-based bioanalytic platform for the quantitation of exo-miRNA markers of sepsis. The candidate is a pharmacist-scientist with a proven commitment to translational science in infectious diseases and precision medicine. Additional skills in transcriptomics and bioanalytical assay development acquired through execution of this proposal will facilitate the candidate?s establishment of a research program devoted to optimizing the management of critically ill patients with life-threatening infectious diseases.
Sepsis is the primary cause of death in hospitalized patients worldwide and mortality is largely attributed to immune exhaustion occurring in response to overwhelming infection and antigenic pressure. We will use a transcriptomic approach to identify exosomal biomarkers for sepsis-induced immunosuppression and develop a bioanalytic platform to guide clinicians in assessment of immune status. Completion of this project should identify novel signaling pathways contributing to immune dysfunction in patients with sepsis.
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