Normal wound healing requires the regulated movement/migration of fibroblasts into the wound, a process under the control of specific growth factors, chemokines and components of the extracellular matrix. The mechanisms by which such factors promote or limit fibroblast motility are not well understood and is the area to which this application is addressed. The most prominent factors within the context of fibroblast migration are those that activate the EGF receptor, TGFalpha and HB-EG F. The long-term goals of this study are to define the specific intracellular signaling pathways which actuate EGFR-mediated motility and to determine how these pathways are modulated by other extrinsic(chemokines) and intrinsic (aging) factors to alter the balance of cell movement into the wound. This application includes three specific aims to address the molecular mechanisms by which the EGFR functions to modulate motility and the effect of aging on this process.
These aims focus on the following hypotheses: 1. That mobilization/activation of actin modifying proteins leads to increased cell motility in response to EGF. 2. That select chemokines counter EGFR-mediated motility in a growth factor-specific manner, and 3. That decreased wound healing in aging is, in part, due to decreased motility response of fibroblasts secondary to decreased signal transduction of the motility pathway.
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