Sepsis arises from a number of different clinical situations and often leads to death of patients in the intensive care unit. The clinical syndrome, sepsis, is defined as the systemic inflammatory response of the host directed specifically at 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-1alpha loxP mice after cecal ligation and puncture which will induce a less severe model of sepsis. These novel mice lack HIF-1alpha only in thymically derived lymphocytes.
Aim 1 will address the hypothesis that HIF-1alpha inhibits the activation of lymphocytes and modulates production of cytokines/ chemokines, thus decreasing the ability of phagocytes to clear the poly-microbial infection leading to decreased survival.
Aim 2 will address the hypothesis that HIF-1alpha modulates lymphocyte numbers by inhibiting proliferation and / or increasing lymphocyte apoptosis during sepsis.
Aim 3 will address the hypothesis that inhibition of the HIF-1alpha-mediated molecular mechanism that directly or indirectly leads to decreased T cell IFN-gamma production will result in increased survival during sepsis. These studies will greatly advance our knowledge of the pathophysiology of 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; 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 |
| 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 |
| 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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