Sepsis arises from a number of different clinical situations and often leads to death of patients in theintensive care unit. The clinical syndrome, sepsis, is defined as the systemic inflammatory response of the host directed specificallyat pathogens. This pathogenetically based definition represents a simple unifying concept for the development of organ dysfunction caused by infection-induced inflammatory states. As such, sepsis represents a significant challenge to the medical community. The long term goal of this project is to determine molecular mechanism by which HIF modulates T cell function during sepsis. These studies will be conducted with Ick-Cre HIF-la loxP mice after cecal ligation and puncture which will induce a lesssevere model of sepsis. These novel mice lack HIF-la only in thymically derived lymphocytes.
Aim I will cddress the hypothesis that HIF-la inhibits the activationof lymphocytes and modulates production of cytokines/chemokines, thus decreasing the abilityof phagocytes to clear the poly-rmcrobial infection leading to decreased survival.
Aim 2 will address the hypothesis that HIF-la modulates lymphocyte numbers by inhibiting proliferationand / or increasing lymphocyte apoptosis duringsepsis. Airr 3 will addressthe hypothesis that inhibitionof the HIF-la-mediated molecular mechanismthat directly or indirectly leads to decreased T cell IFN y production will result in increased survival during sepsis. These studies will greatly advance our knowledge of the pathophysiologyof sepsis and may identify several novel potential therapeutic targets.
| Caldwell, Charles C; Hotchkiss, Richard S (2011) The first step in utilizing immune-modulating therapies: immune status determination. Crit Care 15:108 |
| Kasten, Kevin R; Tschop, Johannes; Adediran, Samuel G et al. (2010) T cells are potent early mediators of the host response to sepsis. Shock 34:327-36 |
| Kasten, Kevin R; Muenzer, Jared T; Caldwell, Charles C (2010) Neutrophils are significant producers of IL-10 during sepsis. Biochem Biophys Res Commun 393:28-31 |
| Unsinger, Jacqueline; McGlynn, Margaret; Kasten, Kevin R et al. (2010) IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 184:3768-79 |
| Kasten, Kevin R; Goetzman, Holly S; Reid, Maria R et al. (2010) Divergent adaptive and innate immunological responses are observed in humans following blunt trauma. BMC Immunol 11:4 |
| Kasten, Kevin R; Prakash, Priya S; Unsinger, Jacqueline et al. (2010) Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun 78:4714-22 |
| Kasten, Kevin R; Tschop, Johannes; Goetzman, Holly S et al. (2010) T-cell activation differentially mediates the host response to sepsis. Shock 34:377-83 |
| Tschöp, Johannes; Nogueiras, Ruben; Haas-Lockie, Sarah et al. (2010) CNS leptin action modulates immune response and survival in sepsis. J Neurosci 30:6036-47 |
| Tschöp, Johannes; Martignoni, André; Reid, Maria D et al. (2009) Differential immunological phenotypes are exhibited after scald and flame burns. Shock 31:157-63 |
| Tschöp, Johannes; Kasten, Kevin R; Nogueiras, Ruben et al. (2009) The cannabinoid receptor 2 is critical for the host response to sepsis. J Immunol 183:499-505 |
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