Transcriptional regulation of matrix metalloproteinases in colon epithelial cells

描述（由申请人提供）： 这是一份修订后的K 08申请表，详细说明了谢国锋博士的5年培训计划。谢国锋博士于2007年12月31日完成胃肠病学奖学金，并加入马里兰州医学院GI系，担任终身助理教授。谢博士将由Richard Eckert博士（系主任）共同指导。和Jurgen Wess（Chief，Molecular Signaling，LBC，NIDDK）。埃克特博士是上皮细胞基因调控领域的著名领导者。Wess博士是研究G蛋白偶联受体的专家，并创造了M3毒蕈碱受体（M3 R）敲除小鼠。高素质的顾问和强有力的咨询委员会将提供更多的科学和职业指导。马里兰州大学为谢博士的学术生涯发展提供了理想的培训环境。指导、教学课程、坚定的机构支持和承诺的结合将最大限度地提高谢博士开展富有成效的科学事业的能力。本研究旨在探讨基质金属蛋白酶（mmp）-7在肠上皮细胞增殖中的作用。小鼠结肠癌模型和培养的结肠上皮细胞中的初步数据表明MMP-7基因在介导M3 R依赖性肠上皮细胞增殖和肿瘤形成中起关键作用。为了检验我们的中心假设，即MMP-7基因诱导对M3 R介导的细胞增殖和瘤形成至关重要，我们提出了3个具体目标来确定：1）体内M3 R的激活诱导EGFR介导的mmp-7基因表达、肠上皮细胞增殖和瘤形成，2）mmp-7基因表达对于M3 R依赖性细胞增殖和瘤形成是关键的，和3）MMP-7的抑制减弱人肿瘤异种移植物的细胞增殖和生长。上皮细胞增殖的调节对于肠发育、对粘膜损伤和肿瘤的反应是重要的。拟议的工作将推进我们对肠上皮细胞生物学的理解，填补有关MMP-7在介导细胞增殖和肿瘤形成中的关键作用的知识空白，从而为专注于MMP-7作为调节上皮细胞增殖的特异性靶点的翻译研究奠定基础。研究计划的完成将使谢博士能够发展一个新颖的，具有临床重要意义的研究重点，并学习重要的实验方法和学术技能，从而为独立的研究生涯奠定坚实的基础。

DESCRIPTION (provided by applicant): 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.