DESCRIPTION (provided by applicant): The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. The goal of this application is to develop a strategy for blood immunomonitoring that can be used as a novel diagnostic and prognostic tool, thereby improving the care of critically ill patients at risk for sepsis. In addition, we seek to model the dynamics of the leukocyte response and identify functional modules and targets for further study. We hypothesize that changes in circulating leukocyte RNA can be used to model the host inflammatory response and improve sepsis diagnostics and prognostics. We reported recently that microarray analysis of circulating leukocytes can be used to captures the dynamics of the host response to and recovery from ventilator- associated pneumonia (VAP). VAP was chosen as the septic insult to study in patients, as it remains a very common, morbid, and expensive ICU complication that is particularly difficult to diagnose. We are testing the clinical value of a graph of RNA information from leukocytes (the riboleukogram), which we expect will mirror the successful efforts made decades ago using a graph of electrical information from myocytes (electrocardiogram). We moved from the bench to the bedside to test this "genomic vital sign" hypothesis using molecular (immune) cartography. The requisite University-wide infrastructure was established to create the Center for Critical Illness and Health Engineering, which spans clinical, translational research, and computational domains. The three interlocking aims of this new R01 application are 1) Map the dynamics of the host response to VAP based upon changes in circulating leukocyte RNA abundance for 85 genes (riboleukograms), 2) Determine the effect of age, gender, and ethnic background on the leukocyte transcriptional response, and 3) Expand our exploration of the biology of the host response to VAP by modeling cell-specific responses. The optimized sample collection protocols are in use. Serial blood samples are drawn over 3-4 weeks from intubated children and adults at risk for VAP. Data are presented demonstrating that riboleukograms track the dynamics of the host response to critical illness complicated by VAP, and that these trajectories are confounded by differences in host gender, age, and ethnic background. Our data also indicate the existence of an immunological attractor state in recovering patients. PUBLIC HEALTH RELEVANCE: Lay Description The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. The goal of this application is to develop a strategy for blood immune monitoring that can be used as a novel diagnostic and prognostic tool, thereby improving the care of critically ill patients at risk for sepsis. In addition, we seek to better understand the response of white blood cells to infection and to identify new therapeutic targets.

Lay Description The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. The goal of this application is to develop a strategy for blood immune monitoring that can be used as a novel diagnostic and prognostic tool, thereby improving the care of critically ill patients at risk for sepsis. In addition, we seek to better understand the response of white blood cells to infection and to identify new therapeutic targets.