Normal wound healing depends on regulated movement of fibroblasts into the und, under the control of growth factors, chemokines, and matrix components. Ho ver, the mechanisms by which these factors interact to promote or limit fibrobla motility are poorly understood, compromising our ability to rationally alte wound healing. Prominent among these factors are those which activate the F receptor (EGFR). TGFalpha and heparin-binding EGF-like growth factor (HB-E ). Our long term goals are to define the specific intracellular signaling path ys which actuate EGFR-mediated motility and to determine how these pathways ar modulated by other extrinsic (chemokines) or intrinsic (aging) factors to a er the balance of cell movement into the wound. We propose to test three hypo eses that probe the molecular mechanisms by which EGFR increases fibroblast moti ty, how motility is limited, and last, how this balance is modulated by age-rel ed deficits. 1. That mobilization/activation of actin modifying proteins leads to incre ed cell motility in response to EGF. We have found that EGFR-mediated motilit requires activation of PLCgamma and hydrolysis of phospho-inositide bisphos ate (PIP2). The critical connection between this action and cell motility mach ery will be determined in fibroblasts expressing signaling-restricted motogenic nd non-motogenic EGFR variants, by ascertaining whether specific PIP2-binding tin modifying proteins are mobilized from the membrane and the effect of this activation on the cytoskeletal connections with the cell membrane. 2. That select chemokines counter EGFR-mediated motility in a growth facto specific manner. Select wound chemokines inhibit fibroblast motility and a considered critical to limiting repair and preventing excess scarring. Preliminary data show that IP-10 blocks EGFR-mediated motility of human der l fibroblasts. We will determine the molecular basis by which IP-10 modulate the motility pathway to suppress EGFR-mediated motility. 3. That decreased wound healing in aging is, in part, due to decreased mot ity response of fibroblasts secondary to decreased signal transduction of the motility pathway. Wound healing is impaired in aging, concomitant with a decrease in fibroblast response to EGF and other growth factors. We propos to demonstrate, in dermal fibroblasts from aged individuals, specific molecula signaling defects in the EGFR-mediated motility pathway which may be overco by upregulation of target molecules or direct activation of downstream process . Completion of these investigations will define an intracellular signaling n work which functions to control EGFR-mediated fibroblast motility. Understandin the balance of these cellular mechanisms is important for designing interventio to promote wound healing and to limit excess fibroblast action in scarring.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Alabama Birmingham
Schools of Dentistry
United States
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Shao, Hanshuang; Yi, Xiao-Ming; Wells, Alan (2008) Epidermal growth factor protects fibroblasts from apoptosis via PI3 kinase and Rac signaling pathways. Wound Repair Regen 16:551-8
Allen, Fred D; Asnes, Clara F; Chang, Philip et al. (2002) Epidermal growth factor induces acute matrix contraction and subsequent calpain-modulated relaxation. Wound Repair Regen 10:67-76
Glading, A; Uberall, F; Keyse, S M et al. (2001) Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. J Biol Chem 276:23341-8
Narang, A; Subramanian, K K; Lauffenburger, D A (2001) A mathematical model for chemoattractant gradient sensing based on receptor-regulated membrane phospholipid signaling dynamics. Ann Biomed Eng 29:677-91
Glading, A; Chang, P; Lauffenburger, D A et al. (2000) Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway. J Biol Chem 275:2390-8
Shiraha, H; Gupta, K; Drabik, K et al. (2000) Aging fibroblasts present reduced epidermal growth factor (EGF) responsiveness due to preferential loss of EGF receptors. J Biol Chem 275:19343-51
Shiraha, H; Glading, A; Gupta, K et al. (1999) IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J Cell Biol 146:243-54
Qin, H; Moellinger, J D; Wells, A et al. (1998) Transcriptional suppression of matrix metalloproteinase-2 gene expression in human astroglioma cells by TNF-alpha and IFN-gamma. J Immunol 161:6664-73
Xie, H; Pallero, M A; Gupta, K et al. (1998) EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway. J Cell Sci 111 ( Pt 5):615-24
Van Epps-Fung, M; Williford, J; Wells, A et al. (1997) Fatty acid-induced insulin resistance in adipocytes. Endocrinology 138:4338-45

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