Analyzing the long-term effects of DNA methylation meditated immunosuppression following sepsis

This proposal is for a five-year research program for Dr. Jon Wisler, an Assistant Professor in the Division of Trauma, Critical Care, and Burn Surgery. This proposal studies the mechanistic events and immunosuppressive clinical consequences of epigenetic methylation events that occur in survivors of sepsis. Dr. Wisler is a highly productive researcher in the fields of epigenetic regulation, sepsis, and clinical outcomes. This proposal couples the knowledge and skills gained during Dr. Wisler’s NIH K08 program relating to epigenetic regulation with direct application to clinical and psycho-social outcomes. Survivors of sepsis exhibit a profound degree of immunosuppression with higher levels of functional decline, depression, subsequent infections, and long-term mortality. To date, investigations related to his topic are fragmented and lack synergy. Jon’s research program seeks to unify multiple areas of investigation to improve the long-term outcomes of survivors of sepsis. His preliminary data identifies that patients with sepsis exhibit significant increases in DNA methyltransferase (DNMT) activity during sepsis. This results in profound gene silencing and immunosuppression. Additionally, we show that survivors of surgical sepsis exhibit numerous negative psycho-social effects that may represent the clinical effects of these epigenetically mediated immunosuppression events. Our intent for this application is to integrate the research efforts of Dr. Wisler and elucidate the deleterious biopsychosocial consequences of these epigenetic events coupled with in vivo assessments of longitudinal immune function and restoration. We hypothesize that molecular or pharmacological means to control DNMT function has potential benefits to patients with sepsis for boosting their innate immune function during the recovery phase of post-septic insult. Incorporating and coordinating these areas of research will greatly improve our understanding of these epigenetic events and provide a unified analysis of mechanistic, translational, and clinical outcomes. Under the R35 program, Jon seeks to integrate cutting-edge laboratory-based investigations and therapeutic testing with patient-based assessments including time-course based immunologic dysfunction and altered clinical outcomes. Post-sepsis immunosuppression is an often diagnosed but untreated consequence of sepsis survivorship. This program will establish the time course, functional effects, and avenues of interventions to treat the underlying epigenetic events involved in this immunosuppression. This will generate paradigm shifting treatments for a disease process with significant clinical impact.