Mechanisms of Altered Neutrophil Trafficking in the Persistent Inflammation, Immunosuppression and Catabolism Syndrome

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Project Summary The proposed Career Development Award will provide Vanessa Nomellini, MD, PhD the support necessary to become an independent scientific investigator. Dr. Nomellini’s research goals are to identify and overcome the undiscovered mechanisms of immune dysfunction after injury and infection. In particular, Dr. Nomellini’s goals are to better understand the patients who progress to a state of chronic critical illness. With the knowledge she gains from the current studies, she hopes to develop clinical trials that will apply early interventions and improve outcomes for these patients. The current proposal aims to investigate the mechanisms of neutrophil dysfunction that occurs during the immunosuppressed phase after sepsis, commonly referred to as the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS). This state is associated with ongoing signs of systemic inflammation, but with increased susceptibility to infection due to T cell depletion and immune cell dysfunction. While a number of immune cells are dysfunctional in this state, this proposed work focuses on the mechanisms of neutrophil dysfunction as the gateway to understanding the pathophysiology behind PICS given the critical role they play in pathogen eradication. The experimental design in this application utilizes a murine model of PICS, which was established in Dr. Nomellini’s lab, to elucidate the mechanisms of aberrant neutrophil migration during PICS using in vivo and in vitro techniques. The career development plan outlined in this proposal includes a mentorship team led by Dr. Charles Caldwell and Dr. Timothy Pritts along with a scholarship oversight committee that includes Dr. Michael Edwards as the Chair of the Department of Surgery and Dr. Alex Lentsch as the Vice Chair of Research for Surgery. While Dr. Nomellini has an extensive background in basic science research, her ability to generate robust clinical trials to further translate the observations in mouse models into the clinic is significantly under- developed. The additional training and mentorship proposed in this application is specifically designed to strengthen and improve her knowledge on clinical trials design to ensure her ultimate career goals are successful. To this end, a reduction in her clinical and educational responsibilities is proposed to provide her with 75% protected research time. She has access to excellent research facilities and equipment to complete all proposed studies. With these changes, along with the complete support of her Department Chair and Section Chief, she will have adequate time and support to successfully complete the proposed studies, follow through with her career development plan and effectively align herself to launch her career as an independent scientist.