The goal of this mentored clinician scientist career development award is to establish a productive translational research program in sepsis immunology that will foster my transition to an independent surgeon- scientist. This training program utilizes a mentored research plan with guidance from Drs. Coopersmith, Kirk, and Ford - experts in sepsis and immunology and established NIH funded researchers, who have a history successful mentorship. My 5 year career development plan gradually builds toward independence. My mentors and I have selected opportunities to broaden my knowledge base, expand technical and experimental design skills, enhance scientific collaboration and communication, develop my laboratory management skills, and mature my grant and manuscript writing. Because more than 210,000 patients die from sepsis per year in the United States, a better understanding of its progression and pathophysiology is critical. Alterations in lymphocyte function and apoptosis have been shown to play an important role in both animal models of sepsis and in septic patients. The scientific approach in this proposal evaluates essential components of the lymphocyte immune response, activation and trafficking, which are poorly understood in sepsis. We propose a multiple compartment and multiple time point analysis of lymphocyte subsets to evaluate the progression of activation and how trafficking is altered in sepsis. In addition, we use a monoclonal antibody to leukocyte function antigen-1 (LFA-1), essential to both lymphocyte activation and trafficking, to evaluate how this process can be modulated for therapeutic benefit. LFA-1 interaction with ICAM-1 promotes lymphocyte activation and co-stimulatory signal transmission and is also involved in firm adhesion and migration of lymphocytes across the endothelium. We hypothesize that LFA- 1 blockade could be beneficial in the early and late phases of sepsis by limiting activation of lymphocytes, decreasing cytokine secretion, and limiting progression to lymphocyte exhaustion. In addition data from ICAM-/- mice shows decreased organ damage in murine sepsis. Thus, blocking LFA-1-mediated trafficking of lymphocytes to inflamed tissue could limit local tissue damage and propagation of the inflammatory response in sepsis. In our preliminary studies, blockade of LFA-1, after induction of sepsis, leads to a significant improvement in survival in a lymphocyte dependent manner. This proposal will identify how lymphocyte activation and trafficking progress in sepsis and how LFA-1 blockade mediates its beneficial effect. In addition, we will use adoptive transfer of activated cells to evaluate how activation contributes to trafficking in sepsis. Finally, we evaluate how these processes alter the immune paralysis and secondary infections seen in the late phase of sepsis. This work will provide both the necessary scientific data and mentorship needed for my transition to an independent scientist and may lead to translation of these findings to critically ill patients.
Sepsis affects 1.1 million patients and causes more than 210,000 deaths per year, making it one of the most prevalent and lethal conditions in the United States. Studies of both animal models of sepsis and septic patients have shown that alterations in lymphocyte function and apoptosis are critical to the progression and outcome of the disease. The experiments outlined in this proposal will improve our understanding of essential components of the lymphocyte response in sepsis, activation and trafficking, and evaluate how they may be modulated to improve the treatment of this very morbid disease.