In pursuit of a PICS prognostic: An investigation of the agents activating and perpetuating PICS.

University Of Florida, Gainesville FL

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Abstract

? DESCRIPTION (provided by applicant): The proposed surgery training plan is an integrated critical care doctoral dissertation research project, supervised by Dr. Lyle Moldawer within the Sepsis and Critical Illness Research Center (SCIRC) at the University of Florida, College of Medicine. The program is ideally designed to equip the candidate to attain his career goals of becoming a physician-scientist. Traumatic injuries are presently the leading cause of death for persons less than 45 years of age. Severe sepsis has more than doubled since 2000, and sepsis currently represents the 11th leading cause of death, and the leading diagnosed hospitalization expense. Although trauma and sepsis patients are now increasingly surviving their initial and early insults due to improved acute medical care, unfortunately two year survivability for these patients has remained unchanged. For trauma and sepsis patients, the greatest obstacle to convalescence is now a chronic immunological disequilibrium that we have termed persistent inflammation, immunosuppression and catabolism syndrome (PICS), and the declining clinical course is characterized by a persistent acute-phase response with systemic inflammation, continuous protein catabolism (despite optimal nutrition), poor wound healing, immunosuppression, and recurrent infections. The agents activating and perpetuating PICS are unresolved, and currently there is no established paradigm to discriminate between those patients who will improve clinically within 14 days from those who will progress to PICS. Early, if not immediately after trauma and sepsis onset, pattern recognition receptors (PRRs) that control inflammatory pathways in the innate and adaptive immune system are likely activated by either damage associated molecular patterns [DAMPs: including endogenous mitochondrial DNA and HMGB1] and/or pathogen associated molecular patterns [PAMPs: including bacterial DNA and bacterial lipopolysaccharide] that are released into the circulation during tissue damage and bacterial infection. The objective of this proposal is to develop an early prognostic of trauma and sepsis clinical trajectory, and to gain insight into the agents activating and perpetuating PICS. The overarching hypothesis is that a time-dependent circulatory load of PAMPs and DAMPs dictates whether trauma and sepsis patients recover or enter PICS. Immediately following trauma and sepsis insult, a small amount of blood (less than 10ml) will be drawn from patients in the intensive care unit. Thereafter, for the duration of ICU stay, blood will be periodically drawn to determine the interactions between the immune system and the levels of DAMPs and PAMPs. Leukocyte genomic expression and PAMP levels will be measured with NanoString. DAMP levels will be measured by a combination of qPCR, ELISA, and NanoString. As DAMPs and PAMPs are thought to be associated with an increasing number of diseases, the successful completion of these studies may ultimately contribute to a better understanding of many or most human diseases.