Regulation of cyclooxygenase-2 by ErbB4 in colon epithelial cells

ErbB4 对结肠上皮细胞中环氧合酶 2 的调节

基本信息

批准号：
8242695
负责人：
Mark R Frey
金额：
$ 8万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242695
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Agar Apoptosis Biological Assay Cell Survival Cells Chemoprevention Clinical Colitis Colon Colon Carcinoma Colorectal Cancer DTR gene Data Development Epidermal Growth Factor Epidermal Growth Factor Receptor Epiregulin Epithelial Cells ErbB4 gene Family Funding Genetic Goals Growth Growth Factor Receptors Half-Life Human In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Ligands Malignant Neoplasms Mediator of activation protein Messenger RNA Molecular Morbidity - disease rate Mucous Membrane Mus North America Nude Mice Participant Pathway interactions Patients Prevention Prostaglandin-Endoperoxide Synthase Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Research Risk Role Signal Pathway Signal Transduction Testing Tumor Necrosis Factor-alpha Xenograft procedure betacellulin cancer cell carcinogenesis cell transformation colon carcinogenesis cost cyclooxygenase 2 cytokine early onset human FRAP1 protein in vivo in vivo Model mRNA Stability member metaplastic cell transformation mortality novel overexpression protein expression receptor research study response tumor xenograft tumorigenesis young adult

项目摘要

DESCRIPTION (provided by applicant): Inflammatory bowel diseases are associated with an increased risk of early-onset colorectal cancer, resulting in great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways active in both inflammation and cancer, which may thus be targets of therapy or chemoprevention. The ErbB4 tyrosine kinase, a member of the epidermal growth factor-related ErbB growth factor receptor family, is expressed at elevated levels in colitis and in a subset of human colorectal cancers. This receptor is thus a candidate participant in colitis-associated tumorigenesis. We recently demonstrated that ErbB4 expression and activity are induced by tumor necrosis factor, and that ErbB4 in turn promotes colon epithelial cell survival in the presence of pro-inflammatory cytokines. Preliminary data developed for this application further show that ErbB4 promotes colon epithelial cell transformation in both in vitro and in vivo models. Furthermore, ErbB4-induced cell survival and transformation are associated with increased mRNA stability and protein levels for the prostaglandin synthase cyclooxygenase-2 (COX-2). Thus, this application proposes to test the hypothesis that ErbB4 promotes colon epithelial cell survival and transformation in the inflammatory milieu through a COX-2-dependent mechanism. Planned experiments will use coordinated in vitro (signal transduction analysis, apoptosis & and colony formation assays) and in vivo (nude mouse xenograft tumor formation assays) approaches to (1) Identify signaling pathways involved in ErbB4-induced COX-2 expression, and (2) investigate cooperation between ErbB4 and COX-2 in colon epithelial cell survival and transformation.

描述（由申请人提供）：炎症性肠病与早发性结直肠癌的风险增加相关，导致经济上以及患者发病率和死亡率方面的巨大成本。深入的研究一直集中在识别炎症和癌症中活跃的信号通路，因此这可能是治疗或化学预防的目标。 ErbB4 酪氨酸激酶是表皮生长因子相关 ErbB 生长因子受体家族的成员，在结肠炎和部分人类结直肠癌中表达水平升高。因此，该受体是结肠炎相关肿瘤发生的候选参与者。我们最近证明，ErbB4 的表达和活性是由肿瘤坏死因子诱导的，并且 ErbB4 反过来在促炎细胞因子存在的情况下促进结肠上皮细胞的存活。为此应用开发的初步数据进一步表明，ErbB4 在体外和体内模型中均促进结肠上皮细胞转化。此外，ErbB4 诱导的细胞存活和转化与前列腺素合酶环加氧酶-2 (COX-2) 的 mRNA 稳定性和蛋白质水平增加有关。因此，本申请提出检验以下假设：ErbB4通过COX-2依赖性机制促进炎症环境中结肠上皮细胞的存活和转化。计划的实验将使用协调的体外（信号转导分析、细胞凋亡和集落形成测定）和体内（裸鼠异种移植肿瘤形成测定）方法来（1）识别参与 ErbB4 诱导的 COX-2 表达的信号通路，以及（ 2)研究ErbB4和COX-2在结肠上皮细胞存活和转化中的合作。