Trauma patients sustain diverse and repeated stresses, including shock, fever and infection, that can lead to multiple organ dysfunction. Recent description of the """"""""two-hit"""""""" paradigm indicates that the sequence permutation of the insults can have a protective or deleterious effect on cell. For example, prior heat shock followed by endotoxic shock protects cells, while induction of heat stress subsequent to endotoxic stress is lethal to animals and cells. In preliminary experiments, the investigator links heat shock paradox to the activity of NF-kB. They show that the fate of a cell depends on whether the endogenous inhibitor of NF-kB, IKBa , is induced before or after the inflammatory stress itself. They have also identified the IkBa as a heat stress gene product. The three interlocking specific aims to be tested are (1) to determine the mechanism by which heat shock decreases binding of NF-kB to its target DNA sequences, (2) to determine the importance of NF-kB to cell fate in the context of heat shock paradox, and (3) to assess the therapeutic potential of resequencing the inflammatory and heat shock stresses in clinically relevant models. These data will not only help how sequences of stresses can induce cytotoxic or cytoprotective effects, but also provide the in vivo role of IkBa as an inducible heat shock protein that regulates inflammatory response which will spark interest in gene-directed therapy for the control of stress-induced organ dysfunction.
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