REGULATION OF INTESTINAL EPITHELIAL GROWTH BY EGF FAMILY

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Important roles for epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha) in gastrointestinal physiology and in specific diseases such as ulcer disease, Menetrier's disease and gastrointestinal neoplasia continue to be identified. The EGF- related peptide family recently has grown to include at least 5 members, including amphiregulin (AR), heparin-binding EGF-like growth factor (HB-EGF) and betacellulin (BTC). Preliminary data reported herein as well as in vivo and in vitro data published by others indicate that there is extensive regulation among EGF family members. For example, expression of each EGF family member is induced by treatment of a variety of epithelial cell lines. In addition, targeted disruption of TGFalpha in vivo by homologous recombination results in replacement of TGFalpha function, presumably by related family members, such that phenotypic alterations are minimal. These observations emphasize the integrated nature of the EGF family. The broad objective of this proposal is to advance understanding of the mechanisms of integration within the EGF family and also the implications of integration for intestinal epithelial cell proliferation by using both in vivo and in vitro techniques. Data is submitted in support of a model whereby AR and HB-EGF are immediate-early genes in intestinal epithelial cells and that their induction is an important contributor to the net proliferative signal induced by EGF-related peptides. Specific aim -1 directly tests this hypothesis by analysis of the relative contribution of AR and HB- EGF to intestinal epithelial cell (RIE-1 line) proliferation by the use of antisense oligonucleotides and neutralizing antibodies Specific aims #2 and #3 represent a concerted effort to place EGF- related peptides into functional perspective in vivo by comparative analysis of their distribution in the small intestine and colon using 1) in situ hybridization and immunohistochemistry, 2) pathophysiological manipulations such as fasting/refeeding and bowel resection and 3) functional studies of transgenic mice that over-express TGFalpha and a new mouse line (egfr/m1cwr) with targeted disruption of the EGF receptor (EGFr). These studies should improve understanding of growth control in normal cells and in selected physiological and pathophysiological circumstances, a prerequisite for a more complete understanding of aberrant growth in neoplasia and other disorders of intestinal epithelial growth.