EXCEED THE SPACE PROVIDED. Although in Fischer-344 rats aging is associated with increased gastrointestinal (GI) mucosal proliferative activity and decreased apoptosis, the regulatory mechanisms are poorly understood. The EGF-receptor (EGFR) likely plays a key role in regulating these processes. Our recent data suggest that aging alters sensitivity of the GI mucosa to EGFR ligands, specifically EGF and TGF-a, such that low doses stimulate mucosal proliferation whereas high doses inhibit this process in aged rats. Thus, we hypothesize that the age-related changes in mucosal proliferation and apoptosis may, in part, be due to increased mucosal sensitivity to EGFR ligands, specifically TGF-a, which is present throughout the GI tract. The age-related rise in EGFR activation in the GI mucosa may also partly be the result of reduction or loss of endogenous EGFR regulatory factor(s). A potential example of these regulatory factors may be ERRP (EGFR Related Protein), a protein we have recently cloned that has 85% homology to the external domain of the rat EGFR. ERRP expression is markedly decreased in the GI mucosa of aged rats and colon cancer cells. Furthermore, overexpression of ERRP in colon cancer cells (HCT-116 and Caco-2) markedly inhibits proliferation and EGFR activation, but stimulates apoptosis. We hypothesize that ERRP is a negative regulator of EGFR that modulates proliferation and apoptosis by attenuating EGFR activation. Since ERRP possesses the ligand binding domain of the EGFR we further hypothesize that ERRP competes with EGFR for ligands and/or may form inactive heterodimers with EGFR resulting in inhibition of EGFR activation. The primary objectives of our work now proposed are:(A) To determine the role of TGF-a and EGFR in regulating gastric and colonic mucosal proliferation and apoptosis during aging by examining (i) binding properties of TGF-a to gastric and colonic mucosal EGFR, (ii) whether and to what extent age-related differences in gastric and/or colonic mucosal proliferation and apoptosis are regulated by EGFR, and (iii) the significance of endogenous TGF-a in regulating gastric and/or colonic mucosal EGFR tyrosine kinase and in turn, proliferation and apoptosis, and (B) To determine the role of ERRP in regulating EGFR and in turn, proliferation and apoptosis in the gastric and colonic mucosa during aging. This will be accomplished by generating ERRP fusion protein and studying the effect of ERRP on EGFR activation, proliferation and apoptosis in the gastric and colonic mucosa during advancing age. ERFORMANCE SITE(S) (organization, city, state) Research Service John D. Dingell VA Medical Center 4646 JohnR Detroit, MI 48201 KEY PERSONNEL ========================================Section End===========================================
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