The Aging Gut: Regulation of Cell Proliferation

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DESCRIPTION (provided by applicant): Increased mucosal proliferation and decreased apoptosis during aging have been well-documented in several tissues of the gastrointestinal (Gl) tract, such as the stomach and colon, of Fischer-344 rats. Although the regulatory mechanisms for these age-related proliferative and apoptotic changes are yet to be defined, we have observed that these events are associated with increased expression and activation of EGFR/ErbB-1 and some of its receptor family members, particularly, HER-2/ErbB-2, suggesting roles for EGFR and ErbB-2 in the regulation of mucosal growth in aging. However, to date, no effort has been made to delineate the individual roles of EGFR and its family members (EGFRs) in Gl mucosal growth during aging. In the current funding period, we isolated a novel growth signaling regulator, CARP-1 (Cell Cycle Apoptosis Regulatory Protein), a 130 kDa perinuclear protein that participates in EGFR-dependent signaling. We have observed that, although activation of EGFRs increases with aging in the Gl mucosa, CARP-1 expression and its tyrosine phosphorylation (Tyr192) are decreased, suggesting that EGFRs and CARP-1 may have a reciprocal relationship. We, therefore, hypothesize that enhanced activation of EGFRs, specifically EGFR and ErbB-2, signaling pathways, in association with diminished CARP-1 expression/activation, predispose the aging gut to increased proliferation and/or decreased apoptosis. To test our hypothesis, we will first determine the individual roles of EGFR and ErbB-2 in the regulation of proliferation and apoptosis in gastric and colonic mucosa during advancing age in Fischer-344 rats. We will then examine the different intracellular pathways, specifically PI3-K, MAPKs and Src-K that may mediate the proliferative and apoptotic effects of EGFR and/or ErbB-2. Finally, we will determine the extent to which CARP-1 participates in EGFR-and/or ErbB-2-dependent Gl mucosal growth by initially quantitating CARP-1 expression and phosphorylation then investigating whether these changes may be due to EGFRs-dependent alterations in the methylation status of the CARP-1 promoter and/or DNA sequences. We anticipate that distinct as well as overlapping pathways are utilized by EGFRs to regulate mucosal growth during aging. The knowledge gained from this study should provide a clearer understanding of these pathways, and the role of CARP-1, in age-related proliferative and apoptotic processes in Gl mucosa.