Burns are one of the most common and devastating injuries known to mankind. Each year in the US approximately 500,000 patients with burns present to emergency departments. Of 40,000 annual hospitalizations, 25,000 burn victims are admitted to specialized burn centers annually. The overall mortality from burns is around 5%, with nearly 4000 deaths reported yearly. In addition, the human, social and economic burden of burns is considerable with an estimated annual expenditure of more than $2 billion direct costs and much greater indirect costs. Funding of this proposal would be a step toward fulfilling an unmet need in the care of patients with severe burns, i.e. treatment to prevent burn injury progression. Such therapy would potentially reduce pain and suffering, minimize need for excision and grafting, decrease infection rate, reduce hospitalization, diminish cost and lessen scarring of burn victims. Proof of principle for such a therapy has been obtained with a fibronectin-derived 14 amino acid peptide (P12) administered intravenously 1 and 24 hr after burn injury in a rat hot comb model. Almost complete inhibition of burn injury progression was achieved in this model with optimal doses of P12. Large animal confirmation of this finding is required prior to the initiation of clinical trials with this novel therapy. Therefore, we propose to confirm the rat studies and optimize the treatment protocol in a validated porcine hot comb model (AIM 1). Porcine models are generally recognized as best for studying injuries to human skin since porcine skin most closely resembles that of humans. In addition, we propose in vivo and in vitro studies to better elucidate P12 mechanism of action (AIMs 2 and 3, respectively). Based on preliminary results with adult human dermal fibroblasts (AHDF), we hypothesize that P12 protects cells from apoptotic or necrotic death induced by oxidative and cytokine stress. In vivo studies to address this hypothesis (AIM 2) will be performed on tissue specimens from the porcine experiments outlined in AIM 1;however, the in vitro studies will utilize human skin cells to bridge the gap from other animal species to human. Results from AIMs 1 - 3 and P12 stability and toxicokinetic studies from AIM 4 are critical for the design of Phase I and II clinical trials (AIM 4). PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page
Clark, Richard August NARRATIVE Burns are one of the most common and devastating injuries known to mankind;each year in the US approximately 500,000 patients with burns present to emergency departments and 4,000 die. The major accomplishment of this proposal would be a step toward fulfilling an unmet need in the care of patients with severe burns, i.e. treatment to prevent burn injury progression. Such therapy would potentially reduce pain and suffering, minimize need for excision and grafting, decrease infection rate, reduce hospitalization, diminish costs and lessen scarring of burn victims. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page
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