This is a revised K08 application detailing a 5-year training plan for Dr. Guofeng Xie, who completed Gastroenterology Fellowship on 12/31/2007 and joined the Gl faculty at the University of Maryland School of Medicine as a tenure-track Assistant Professor. Dr. Xie will be co-mentored by Drs. Richard Eckert (Chair, Dept. of Biochemistry and Molecular Biology) and Jurgen Wess (Chief, Molecular Signaling, LBC, NIDDK). Dr. Eckert is a renowned leader in the area of epithelial cell gene regulation. Dr. Wess is an expert in the study of G protein-coupled receptors and has created M3 muscarinic receptor (M3R) knockout mice. Highly qualified consultants and a strong Advisory Committee will provide additional scientific and career guidance. The Univ. of Maryland provides an ideal training environment for Dr. Xie's academic career development. The combination of mentoring, didactic coursework, unwavering institutional support and commitment will maximize Dr. Xie's ability to launch a productive scientific career. The proposed study focuses on the role of matrix metalloproteinase (mmp)-7 in mediating intestinal epithelial cell proliferation. Preliminary data in murine colon cancer models and in cultured colon epithelial cells indicate a key role for the mmp-7 gene in mediating M3R-dependent intestinal epithelial cell proliferation and neoplasia. To test our central hypothesis that mmp-7 gene induction is critical for M3R-mediated cell proliferation and neoplasia, we propose 3 Specific Aims to establish that: 1) Activation of M3R in vivo induces EGFR-mediated mmp-7 gene expression, intestinal epithelial cell proliferation and neoplasia, 2) mmp-7 gene expression is critical for M3R-dependent cell proliferation and neoplasia, and 3) Inhibition of MMP-7 attenuates cell proliferation and growth of human tumor xenografts. Regulation of epithelial cell proliferation is important for intestinal development, response to mucosal injury and neoplasia. The proposed work will advance our understanding of intestinal epithelial cell biology, filling important gaps in knowledge regarding the critical role of mmp-7 in mediating cell proliferation and neoplasia, thereby laying the groundwork for translational studies focusing on MMP-7 as a specific target for modulating epithelial cell proliferation. Completion of the research plan will allow Dr. Xie to develop a novel, clinically important research focus and learn important experimental methods and academic skills thereby laying a solid foundation for an independent research career.
