GENOMIC PREMODULATION OF POST-TRAUMATIC RECOVERY

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Endotoxin (ETX) can be a lethal agent, but it also can be used to prime cells, organs, or animals to resist a subsequent injury. Though this state of protection has an undefined mechanism, it is highly conserved in that one priming stimulus protects against another, and that diverse stimuli appear to induce the expression of a common pattern of genes. We hypothesize that multiple types of priming stimuli can each therapeutically prime cells or tissues by causing the expression of a common program of genes which is related to protection from subsequent injury. We will address this hypothesis at the organ level (isolated heart, gut ischemia models) and gene levels by characterizing the program of tissue gene expression of early response genes, heat shock proteins, anti-oxidant enzymes, growth factors, and fetal program genes in response to a range of pathologic and physiologic stimuli. This programmed response will be localized within organs by in situ mRNA and protein hybridizations. Models of tissue gene injection and subsequent gene manipulation should allow mechanistic investigations of the preceding characterization. Results to date suggest a conserved genomic response mimicking the fetal state to stimuli which have in common the protein synthesis dependent induction of protection. Skeletal muscles injected with a promoter/reporter gene construct show expression of the injected gene. Finally, initial experiments suggest some parallels between rat and human myocardial gene expressions after similar stimuli. Knowledge gained from these proposed basic investigations should lead to improved clinical treatments.