Exercise is a complex stress involving elevated core temperature as well as intracellular oxiradical generation, cellular energy depletion, local tissue ischemia, and increased inflammatory cytokine levels that correlate to the appearance of bacterial endotoxins in the circulation. At the cellular level tolerance to heat is associated with the intracellular accumulation of heat shock proteins (HSPs). This HSP accumulation is also associated with cellular tolerance to oxiradicals, energy depletion, and cytokines, as well as a modified endotoxin response with increased survival in the whole organism. The causative link between HSP accumulation and thermotolerance is still circumstantial. Moreover, the link between classical thermotolerance - the cell's survival of an otherwise lethal heat stress - may be less important in the adaptation of the intact organism than is the ability of a tissue of organ system to remain functional during the stresses of hyperthermia, which we have termed """"""""physiological thermotolerance."""""""" This physiological thermotolerance which is defined as maintenance of function of a cell or tissue rather than defined in terms of survival, may be more relevant to the adaptive response of the intact organism. We have developed a series of gene transfer vectors to allow us to overexpress specific HSPs in cells on culture as well as in the intact organism. Using a functional assay of heat tolerance we will move sequentially from cells in culture to an isolated epithelial monolayer, to an animal model to determine the effects of HSP overexpression in response to heat, oxidative stress, energy depletion, and in the intact organism, endotoxin exposure. Because the HSP gene transfer vectors allow us to overexpress HSPs in virtually all cells in a population and effectively transduce organs such as the liver in vivo, we will be able to study the relationships between the cellular adaptive response to heat stress and the adaptation of both a multicellular tissue and the intact organism resulting from specific HSP overexpression.
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