Caring for critically ill patients suffering from multiple organ dysfunction syndrome (MODS) represents one of the most difficult challenges in critical care medicine. The high mortality of adults and pediatric patients with MODS warrants a greater understanding of pathophysiology at the molecular level. Elucidating the molecular mechanisms that cause MODS is a daunting task because critically ill patients are typically subjected to multiple, simultaneous, and/or sequential injurious stimuli. The """"""""multiple hits"""""""" hypothesis of MODS states that the interactions of multiple stimuli, and the unexpected cellular responses that they may generate, can ultimately lead to organ failure. The investigators propose to undertake a reductionist approach whereby they will study the in vitro interactions of two fundamental, yet distinct, cellular responses that are ubiquitous during various forms of critical illness: the heat shock response, and activation of the transcription factor NF-kappaB. They have demonstrated that the heat shock response, a primitive cellular defense mechanisms, inhibits activation of NF-kB, which is involved in the regulation of many proinflammatory genes. Preliminary data indicate that inhibition occurs by two mechanisms. The proximal mechanism involves inhibiting phosphorylation and subsequent degradation of the NF-kappaB inhibitory protein, I-kappaBalpha. The distal mechanism involves heat shock response-mediated de novo expression of the I-kBa gene.
Specific Aim I is designed to determine the mechanism by which the heat shock response inhibits phosphorylation of I-kBa.
Specific Aim II is designed to determine the mechanism by which the the heat shock response induces expression of I-kBa, and proposes a fundamental reclassification of I-kB as not only an inhibitor of NF-kB, but also as a novel heat shock protein.
Specific Aim III is designed to determine if heat shock response-mediated expression of I-kBa independently inhibits activation of NF-kB. By elucidating the mechanisms proposed in this application, they will provide novel insight regarding the interactions of these two fundamental cellular responses. Ultimately, it is hoped that this mechanistic insight, at the molecular level, will lead to a greater understanding of mechanism at the physiologic level, which in turn can form the basis of more rational and specific therapeutic strategies.
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