The PI has demonstrated in the Fischer-344 rat that proliferation of epithelial cells in the stomach increases with advancing age. Others have shown similar increased proliferation in the small and large intestine of older rodents. The mechanism underlying this phenomenon is not known. Work published since 1989 by the Principal Investigator has shown an increase in the sensitivity of the gastric mucosa to the action of EGF and TGF-a since the dose response curve for these peptides was shifted to the right and doses that were stimulating in the stomach of young rats were inhibitory in aging rats. Accompanying these changes, the Principal Investigator and collaborators have noted an increase in EGF-R tyrosine kinase activity and a concordant rise in the phosphorylation of a number of non-receptor cellular proteins, particularly a protein with an Mr of 55 Kda (named pp55). The proposed studies aim to clarify the effects of the EGF family of peptides and to determine the role of pp55. The Principal Investigator plans: (a) to study whether increased sensitivity is due to increased binding of EGF to the receptor (EGF-R) or/and post receptor changes; and (b) to evaluate effects of increasing doses of EGF versus immunoneutralization by the administration of EGF antibodies. In a separate series of studies with separate purposes, the investigators wish to understand the functions of the novel tyrosine kinase (pp55) that is not associated with the EGF receptor and appears to be stimulated under a variety of conditions, particularly in the aging gastric mucosa. Their plan is to isolate the cDNA clones encoding pp55, complete nucleotide sequencing and when a full length transcript is available, to overexpress this transcript in the baculovirus gene expression system. They have performed similar studies in the colonic mucosa of aging rats in which they find greater stimulation of EGF-R tyrosine kinase activity in older animals.
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