Growth Factor Modulation of Reepithelialization

Hudson, Laurie

Abstract

This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Restoration of epithelial barrier function is essential in the healing of wounds incurred by surgery, trauma, burns or chronic failure to heal. A crucial component of successful wound healing is reepithelialization in which the acquisition of a motile phenotype is accompanied by alterations in cellular adhesion. Growth factors play an important role in successful wound reepithelialization since they regulate proliferation, migration or both activities in target cells. Although in vivo studies have demonstrated promotion or acceleration of wound healing by exogenous addition of growth factors, relatively little is known about the relative contribution of the mitogenic versus motogenic actions of growth factors to the various stages of reepithelialization on how different growth factors may play differential roles in the process. Desmosomes have been reported to disappear during the migratory phase of wound healing and the reappearance of desmosomes marks the end of the migratory phase. Our hypothesis is that growth factors which directly promote keratinocyte migration also play a role in regulating desmosome disassembly and altered cell adhesion. Our goal is to more clearly define the requirements for growth factor modulated keratinocyte migration and adhesion in an in vitro model that mimics the reepithelialization phase of wound healing. Migration and loss of adhesion can occur independently, but when they occur coordinately, this may involve multiple pathways or varied aspects of growth factor mediated responses. We wish to address mechanisms by which growth factors may regulate these complex processes. This proposal will specifically address 1) the optimization of a growth factor regulated model of reepithelialization and keratinocyte motility, 2) investigate the distribution of desmosomal cadherins and associated proteins in response to growth factors, 3) examine mechanisms by which growth factors could affect desmosomal cadherin function and 4) directly examine the consequences of modulating desmosomal cadherin expression on cell migration and reepithelialization in vitro. As we understand the molecular basis for the therapeutic benefits of growth factors in wound healing, more reasoned and successful treatment strategies may be designed.