This mentored Clinical Scientist Career Development Award (K08) will provide training and support in my ongoing advancement to becoming an independent researcher. I am a Trauma / Critical Care surgeon at Rhode Island Hospital with an appointment as an Assistant Professor of Surgery at Brown University. My career path has always been aimed at the care of the critically ill and traumatically injured surgical patient, wit an emphasis sepsis. This is evidenced by training at a busy Level 1 trauma center under the tutelage of a renowned expert in surgical infections. This time allowed the formation of sound research principles and offered a focus for future endeavors. This was followed by a fellowship in trauma and surgical critical care and an in-depth study of critical illness emphasizing sepsis and end-organ failure. On taking a position at Rhode Island Hospital / Brown University, I followed advice to establish myself clinically during the first several years while building the scientific frame-work needed for a successful surgeon scientist career. This included working closely with my primary mentor, Alfred Ayala PhD, a well-funded, internationally recognized investigator studying sepsis as well my co-mentor Dr. Laurent Brossay, an internationally recognized investigator in iNKT- cells. This culminated in being award a Junior Faculty Grant from the Shock Society, as well as a grant from the SURDNA foundation to assess immune dysfunction in critically ill and injured geriatric patients. Since the initial submission Dr. Laurnt Brossay has become, and will continue to serve as, a co-primary mentor. I have continued to work on the interaction between iNKT-cells and macrophages advancing the potential link via HMGB-1. I have continued to publish on iNKT/sepsis/critical care. I work within the Division of Surgical Research at Rhode Island Hospital. I continue to benefit, from an environment that is rich in the areas of inflammation, infection and immunity. I have afforded myself of the opportunities of course work within the Department of Pathobiology and Department of Molecular Microbiology and Immunology at Brown University. There are ample resources (personnel and equipment) both at Rhode Island Hospital as well as on the Brown campus to ensure the success of the proposed project. Both Rhode Island Hospital and Brown University have been designated as Centers of Biomedical Research Excellence (COBRE). I have benefited from ongoing protected time for research and I am assured of at least 75% protected time for this proposal. My Individualized Development plan is well-rounded and has short and long term goal. This also includes a research committee consisting of senior faculty with track records of teaching and mentoring graduate and post-graduate students as well as junior faculty. My research committee will continue to include a well-funded surgeon scientist, who continues to advise and guide my surgical career as an independently funded surgeon scientist, with a long term goal of directing surgical research. I will continue to take courses offered at Brown University and Rhode Island Hospital as they relate to innate immunology, statistics, study design, responsible conduct of research, as well as national seminars. My immediate career goal is to establish and complete a multi-year research project investigating immune dysfunction following sepsis, establishing independence as a surgeon scientist investigator. The longer term scientific goal will be to translate these findings back to the bed-side, thereby positively impacting the care of the critically ill septic patient. To this aim, I have already demonstrated that several important aspects of lymphocyte/iNKT related immune dysfunctions noted in a mouse model were also noted to be present in critically ill septic patients. I have demonstrated a similarity across both mice and humans with respect to lymphocyte and invariant Natural Killer T-cell (iNKT-cell) profiles following sepsis, critical illness and injury.This includes several key co-inhibitory receptors (eg PD-1, BTLA), as well as a potential role for HMGB-1. This proposal continues to expand our understanding of how sepsis alters iNKT-cells and how iNKT-cells induce subsequent changes in phagocytes. To date my preliminary data has demonstrated that following sepsis, activated iNKT-cells appear to migrate to the peritoneal cavity, alter macrophage phagocytic capacity and phenotype, and play a role in modulating the HMGB-1 response to sepsis. I have demonstrated a key association between circulating iNKT-cells and mortality in critically ill septic ICU patients. To expand upon these initial findings an offer a more mechanistic basis, the proposed experiments will test the hypothesis that sepsis activates, alters and mobilizes invariant NKT-cells, and that these septic iNKT-cells modulate the macrophage response to septic shock. The proposal is structured in three specific aims: 1) To determine if sepsis induces changes in iNKT-cells phenotype, function and degree of anergy: 2) Using iNKT-cell knock-out mice, we will define the role of iNKT-cells in altering septic peritoneal macrophage function: 3) To extent that a bridging mechanism, such as a DAMP, Alarmin, PAMP, etc, that mediates the cell:cell interaction between iNKT-cells and macrophages exists, we will assess the specific role of HMBG-1 as a common extrinsic mediator (DAMP), in regulating the iNKT-cell:macrophage interaction seen in sepsis. It is anticipated that findings from this work will potentially identify therapeutic targets for future sepsis strategies. I believ that I am an ideal candidate for this mentored career development award (K08) in my road to independence as a surgeon scientist.
Sepsis contributes substantially to healthcare costs, morbidity, and mortality among critically ill surgical patients. The implementation of new modalities in critical care, including early goal-directed fluid therapy and antimicrobial regimens has failed to ameliorate these significant problems. This study seeks to determine how invariant natural killer T-cells (iNKT-cells) participate in and influence other elements of the coordinated immune response to sepsis. To do this, we will utilize the cecal ligation and puncture (CLP) model of polymicrobial sepsis to evaluate how sepsis induces changes in iNKT-cell structure and function, and how such changes alter other immune cells. We strongly believe that such knowledge will be critical not only to understanding the complex regulation of the immune system in response to infection, but also in identifying potential targets in sepsis.
