Transcriptional regulation of matrix metalloproteinases in colon epithelial cells

结肠上皮细胞基质金属蛋白酶的转录调控

基本信息

批准号：
7688541
负责人：
Guofeng Xie
金额：
$ 13.04万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-20 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688541
关键词：
Ablation Acetylcholine Advisory Committees Animals Antibodies Area Attenuated Azoxymethane Biochemistry Cancer Biology Cancer Model Cell Culture Techniques Cell Line Cell Proliferation Cellular biology Cholinergic Agonists Clinical Trials Colon Colon Carcinoma Colonic Neoplasms Data Development Environment Epidermal Growth Factor Receptor Epithelial Cell Proliferation Epithelial Cells Faculty Feedback Fellowship Figs - dietary Foundations G-Protein-Coupled Receptors Gastroenterology Gene Expression Gene Expression Regulation Genes Genetic Transcription Genus Cola Growth Human Implant In Vitro Inhibition of Matrix Metalloproteinases Pathway Injury Intestinal Neoplasms Intestines Knockout Mice Knowledge Learning Ligands Maryland Matrilysin Matrix Metalloproteinases Mediating Membrane Mentors Methods Modeling Molecular Molecular Biology Mus Muscarinic Acetylcholine Receptor Muscarinic M3 Receptor National Institute of Diabetes and Digestive and Kidney Diseases Neoplasms Nude Mice Physiological Play Pongidae Qualifying Receptor Activation Receptor Signaling Regulation Research Research Personnel Role Safety Signal Transduction Small Interfering RNA Solid Stimulation of Cell Proliferation Testing Tissues Training Transcriptional Activation Transcriptional Regulation Tumor Burden Universities Up-Regulation Work Xenograft procedure base cancer cell career career development cholinergic colon cancer cell line gene induction heparin-binding EGF-like growth factor in vivo innovation medical schools neutralizing antibody novel pre-clinical professor programs receptor expression response skills therapeutic target translational study tumor tumor xenograft tumorigenesis

项目摘要

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.

描述（由申请人提供）：这是修订后的 K08 申请，详细介绍了谢国锋博士的 5 年培训计划，谢国锋博士于 2007 年 12 月 31 日完成了胃肠病学奖学金，并加入马里兰大学医学院的 GL 系，担任终身教授助理教授。谢博士将由博士共同指导。 Richard Eckert（生物化学和分子生物学系系主任）和 Jurgen Wess（LBC、NIDDK 分子信号传导主任）。 Eckert 博士是上皮细胞基因调控领域的著名领导者。 Wess博士是G蛋白偶联受体研究的专家，并创造了M3毒蕈碱受体（M3R）敲除小鼠。高素质的顾问和强大的咨询委员会将提供额外的科学和职业指导。大学。马里兰大学为谢博士的学术生涯发展提供了理想的培养环境。指导、教学课程、坚定不移的机构支持和承诺相结合，将最大限度地提高谢博士开启富有成效的科学事业的能力。拟议的研究重点是基质金属蛋白酶（mmp）-7 在介导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的初步数据表明 mmp-7 基因在介导 M3R 依赖性肠上皮细胞增殖和肿瘤形成中发挥关键作用。为了检验我们的中心假设，即 mmp-7 基因诱导对于 M3R 介导的细胞增殖和肿瘤形成至关重要，我们提出了 3 个具体目标来确定：1) 体内 M3R 的激活诱导 EGFR 介导的 mmp-7 基因表达，肠上皮细胞细胞增殖和肿瘤形成，2) mmp-7 基因表达对于 M3R 依赖性细胞增殖和肿瘤形成至关重要，3) 抑制 MMP-7 会减弱细胞增殖和肿瘤形成人类肿瘤异种移植物的生长。上皮细胞增殖的调节对于肠道发育、对粘膜损伤和肿瘤的反应非常重要。拟议的工作将增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关键作用的知识空白，从而为关注 MMP-7 作为特定靶点的转化研究奠定基础。调节上皮细胞增殖。研究计划的完成将使谢博士能够开拓一个新颖的、临床上重要的研究热点，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。