Many studies have documented rapid recovery of the gastric mucosa following minor to moderate injury, yet little is known about the intracellular mechanisms responsible for healing, or whether mucosal regeneration is affected by aging. On the basis of our preliminary data we hypothesize that (a) aging is associated with diminished regenerative capacity, and that (b) this may in part be due to decreased activation of tyrosine kinases (Tyr-k) and a reduction in tyrosine-specific phosphorylation of regulatory proteins, specifically the epidermal growth factor receptor (EGF-R), which possesses Tyr-k activity, and (c) this results in decreased transcription of regulatory genes, leading to (d) diminished cell proliferation and epithelial regeneration. We now propose using the in vivo model of hypertonic saline-induced injury in the Fischer-344 rats to determine (1) whether the age-related differences in mucosal regeneration could be due to alterations in mucosal proliferative activity, cell proliferation and migration, and (2) whether the differences in cell proliferation are the result of age-related changes in the rate of mucosal cell loss, and (3) whether the changes in cell proliferation/cell migration correlate with histologic restitution of the mucosa; (4) furthermore, we will also evaluate the role of tyrosine kinases, specifically the 170 kDa phosphotyrosine membrane protein (which we have tentatively identified as EGF-R) in the regulation of gastric mucosal cell proliferation during regeneration. Finally, (5) we will determine whether the age-related changes in mucosal regeneration are under the control of the proto-oncogene c-erbB-1 which encodes a truncated EGF-R containing the cytoplasmic kinase domain. The information derived from these studies has the potential to expand our understanding of regenerative processes of the gastric mucosa and to identify some of the mechanisms that may be responsible for maintaining mucosal integrity.
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