Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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The overall goal of the proposed study is to determine whether aged mice are less able to withstand a moderate size scald injury than are young adult mice. The elderly burn patients are four times more likely to from a moderate size thermal injury than are healthy young adult patients. The production of macrophage-derived proinflammatory cytokines, including interleukin-6 (IL-6) and prostaglandin E2 (PGE2), is markedly elevated following burn trauma and there is a positive correlation between elevation in the circulating levels of these mediators and a poor prognosis. Since elderly individuals have constitutively high circulating levels of some of these mediators, most notably IL-6, it is possible that they are predisposed to a fatal outcome by virtue of having elevated levels of these mediators prior to injury. Furthermore, other work in our laboratory suggests that post trauma elevation in circulating corticosterone plays a protective role by attenuating the production of this same set of mediators. Furthermore, in preliminary studies, aged mice fail to maintain high levels of corticosterone after burn injury. From these pieces of evidence, we hypothesize that aged mice are less able to tolerate burn trauma than are young adult mice because of the overproduction of macrophage-derived mediators, IL-6 and PHE2, which are not adequately controlled by endogenous glucocorticoids. To address this, we will 1) examine survival of aged versus young adult mice following thermal injury, 2) monitor IL-6 and PGE2 levels in peripheral blood and in supernatants from cultured macrophage, and 3) compare the time course and magnitude of circulating levels of corticosterone. Finally, if it is determined that aged mice fail to maintain high levels of corticosterone after thermal injury than attempts to manipulated the glucocorticoid levels by administration of exogenous corticosterone or the glucocorticoid receptor antagonist RU486 to alter survival rates. Such studies will yield valuable information about the mechanisms by which aging effects survival in the burned individual.
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