Sepsis is a life-threatening condition, the leading causes of death in intensive care units and is caused by Gram-negative and/or Gram-positive bacteria or the products of these bacteria. The infections result in activation of pattern recognition receptors such as the toll-like receptor (TLR) family leading to expression of the pro-inflammatory cytokines such as interleukin-1 b (IL-1b) and tumor necrosis factor-a (TNFa). Considerable research over the past several decades suggested that hyper-inflammation was the cause of high mortality in sepsis and this led to several clinical trials of anti-inflammatory strategies in an effort to reduce the mortality in sepsis. These trials all failed with the exception of activated protein-C. Bacteria can also induce apoptotic cell death in a several organs either directly through TLRs or by causing secondary activation of death receptors (DRs). The hypothesis of this grant application states that multiple organ failure (MOF) in sepsis occurs as a result of apoptosis within the organ and cell death is induced by death signaling through DRs) and TLRs. We will investigate this hypothesis through 5 specific aims. 1) To determine whether over-expression of a dominant negative Fas Associated Death Domain (FADD-dn) protein can improve survival in severe sepsis induced by cecal ligation and puncture (CLP). 2) To determine the contribution of hematopoietic and non-hematopoietic Fas in sepsis following CLP using bone marrow chimeras. 3) To determine the contribution of TLR/MyD88-dependent signaling in hematopoietic versus non-hematopoietic cells in sepsis following CLP using bone marrow chimeras. 4) To examine whether double deletion of Fas and MyD88 alters survival in severe sepsis following CLP. 5) To examine the effect of over-expressing FADD-dn or the caspase inhibitor p35 protein from baculo-virus in intestinal epithelial cells or in cardiomyocytes following induction of severe sepsis by CLP. Relevance: Severe bacterial infection can lead to death in critically ill patients and there is a need for improved thereaputics to treat this major health problem in the United States. This project will aid in our understanding of the cause of death and may suggest new therapies.
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