Sepsis accounts for 250,000 deaths annually in the United States alone. Unrestrained stimulation of phagocytes can induce Systemic Inflammatory Response Syndrome (SIRS) resulting in failure of multiple systemic organs. Prolonged SIRS leads to enhanced susceptibility to nosocomial infection. Phagocyte recognition of microbial products is mediated by Toll like receptors via activation of Toll/IL-1R (TIR) adaptor MyD88-dependent NF-kB activation. There are numerous endogenous brakes involved in TLR activation, including phosphatases SHIP-1 and DUSP. The role of the phosphatase and tensin homolog PTEN in controlling macrophage activation and its role in controlling polymicrobial sepsis is unknown. This project is based on preliminary data showing that PTEN inhibits MyD88 expression by controlling actions of specific microRNAs. Furthermore, while PTEN activation has protective effects in acute sepsis, enhanced and chronic PTEN expression produces deleterious effects favoring endotoxin tolerance and possibly secondary infection. The hypothesis to be tested is that although PTEN protects against overwhelming inflammatory responses early in acute sepsis, excessive PTEN expression is responsible for both the initiation and maintenance of sepsis-induced immunoparalysis states by impairing TLR activation in phagocytes. These studies will increase our overall understanding of how innate immunity works, and will produce insights regarding the pathogenesis of acute sepsis and enhanced susceptibility to secondary infection in deleterious conditions. We propose the following specific aims: 1 - Determine how PTEN controls transcriptional and post-transcriptional modifications involved in MyD88 expression; 2- Determine how PTEN influences sepsis outcome and morbidities associated with secondary lung infection. The identification of specific components and their modes of action in maintenance of sepsis may identify targets for therapeutic intervention resulting in improved immune responsiveness in settings of host vulnerability, and may suggest strategies to dampen the immune response in settings of exaggerated inflammation.
Sepsis remains the leading cause of mortality in intensive care units, and is the most common cause of late organ injury after trauma and surgical intervention. Although sepsis starts with overwhelming inflammation and is followed by organ damage, it also produces a state of impaired immunity, which is often followed by nosocomial infection. This project seeks to investigate the role of a molecular brake in both homeostatic innate immune responses, as well as in deleterious conditions, to identify novel regulatory pathways involved in early events involved in sepsis, and elucidate pathways contributing to impaired immunity in later stages of sepsis involved in secondary infection.
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