Wounds are characterized by a hostile environment, due in large part to hypoxia and the inflammatory milieu. Remaining viable cells not only must withstand these conditions, but also must undergo a coordinated series of migratory, proliferative and synthetic events for proper wound repair. Here we plan to test the idea that early after wounding there occurs a series of specific changes in both signal transduction pathways and gene expression that allows for remaining cells to both survive and subsequently undergo these healing processes. Immediately after injury we propose that remaining viable cells activate the expression of the heat shock or stress proteins, thereby facilitating the ability of the cells to survive under the adverse conditions characteristic of the early wound. Subsequently, additional changes in gene expression must occur in order for the normally quiescent cells to become proliferative, synthesize and deposit extracellular matrix components and then eventually return to their quiescent state. We propose that this 'second step' of wound healing will involve the activation of a group of 'master' regulatory genes referred to as the Homeobox genes. Utilized during early growth and differentiation processes, we hypothesize that some of the homeobox genes are specifically 'reactivated' in order to coordinate the temporal expression of other genes that are required for efficient wound repair. Hence, in initial experiments we will utilize immunocytochemical as well as in situ hybridization techniques to analyze for changes in both stress protein and homeobox protein expression within incisional wounds. Hence, in initial experiments we will utilize immunocytochemical as well as in situ hybridization techniques to analyze for changes in both stress protein and homeobox protein expression within incisional wounds. In parallel, primary cultures of dermal fibroblasts, basal keratinocytes and endothelial cells will be cultured under conditions that recapitulate the wound microenvironment and again the resultant changes in both stress protein expression and homeobox protein expression determined by different means. Should changes be observed, subsequent studies will examine the consequences of prior manipulation of either the stress proteins or homeobox proteins on the ability of the ells to both survive and eventually undergo proliferative responses following a particular injury. Finally, studies will be undertaken to determine the consequences of manipulating stress protein and homeobox protein expression in animal models of wounding. Here particular attention will be directed at determining whether manipulation of these proteins can enhance the overall process of wound repair. In sum, we will test the idea that efficient wound repair involves the coordinated expression of genes involved in cellular protection (stress proteins) and cellular remodeling events (homeobox proteins).
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