TGF-Beta Regulation of Intestinal Epithelial Cells

TGF-β 对肠上皮细胞的调节

• 批准号: 7425948
• 负责人: JOHN A BARNARD
• 金额: $ 29.03万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425948
• 关键词: Animal Model; Apoptosis; Appendix; Binding; Cancer Etiology; Cell Line; Colon Carcinoma; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Complex; Data; Defect; Deposition; Diagnosis; Disease; Dissection; Epigenetic Process; Epithelial; Epithelial Cells; Extracellular Matrix; Face; Fibrosis; Gastrointestinal tract structure; Gene Expression Profile; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome Stability; Genomics; Goals; Growth; Histones; Hyperactive behavior; Immunosuppression; Intestinal Neoplasms; Intestines; Lead; Malignant Neoplasms; Mediating; Mesenchymal; Microarray Analysis; Molecular; Morbidity - disease rate; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peptides; Regulation; Resistance; Signal Pathway; Signal Transduction; Staging; Testing; Therapeutic; Therapeutic immunosuppression; Transforming Growth Factor beta; Translating; Tumor Promoters; Tumor Promotion; Tumor Suppression; Tumor Suppressor Proteins; United States; angiogenesis; attenuation; autocrine; cancer cell; cell transformation; concept; design; human HDAC1 protein; human migration; improved; in vitro Model; in vivo; intestinal epithelium; metallothionein III; mortality; neoplastic; novel; novel strategies; prevent; receptor; research study; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal neoplasia is a leading cause of cancer morbidity and mortality in the United States. Although the genomics revolution has resulted in high profile advances in cancer therapeutics, these have not translated into a definitive improvement in the survival of patients with advanced disease. Thus, it is critical to continue the study of the molecular pathogenesis of colon cancer with the goal of improved diagnosis and treatment. Over the past decade, we have studied the autocrine growth inhibitory factor, transforming growth factor beta(TGFbeta), in normal and aberrant intestinal epithelial growth. During this interval, TGFbet, its receptor, and the Smad signaling pathway have been decisively recognized as a critical axis of tumor suppression in the intestinal epithelium. In certain contexts however, TGFbeta signaling may contribute to tumor promotion, a duality of function that is increasingly recognized in neoplastic disorders. We propose to explore this dual activity of TGFbeta in in vivo and in vitro models of intestinal neoplasia, especially in the context of oncogenic Ras, which we have defined as a key repressor of growth inhibitory Smad-dependent TGFbeta signaling. The overarching hypothesis is that TGFbeta is a tumor suppressor via Smad-dependent signaling early in tumorigenesis. At later stages of disease TGFbeta signaling switches, in part under the influence of oncogenic Ras, to tumor promotion. The specific aims are to 1) test the hypothesis that histone deacetylases are Smad-binding partners and modulators of Smad-dependent signaling; 2) test the hypothesis, using microarray analysis, that TGFbeta induces a unique transcriptome in Ras-transformed cells and then use the results to further characterize TGFbeta as a tumor promoter; 3) test the hypothesis that TGFbeta will have both tumor suppressing and tumor promoting functions in animal models of TGFbeta signaling and colorectal cancer using genetically engineered mice in which TGFbeta signaling is enhanced. Dissection of the pathways involved in the tumor suppressive versus the tumor promoting effects of TGFbeta will lead to opportunities to selectively inhibit its undesirable effects without compromising its tumor suppressive functions.

描述（由申请人提供）：结直肠肿瘤是美国癌症发病率和死亡率的主要原因。尽管基因组学革命已经在癌症治疗方面取得了引人注目的进展，但这些进展并没有转化为晚期疾病患者生存率的明确改善。因此，继续研究结肠癌的分子发病机制以改善诊断和治疗是至关重要的。在过去的十年中，我们研究了自分泌生长抑制因子，转化生长因子β（TGF β），在正常和异常的肠上皮生长。在此期间，TGFbet、其受体和Smad信号传导途径已被确定性地认为是肠上皮中肿瘤抑制的关键轴。然而，在某些情况下，TGF β信号传导可能有助于肿瘤促进，在肿瘤性疾病中越来越多地认识到功能的双重性。我们建议探索这种双重活性的TGF β在体内和体外模型的肠道肿瘤，特别是在致癌Ras的背景下，我们已经定义为生长抑制Smad依赖性TGF β信号转导的关键阻遏物。总体假设是TGF β是肿瘤发生早期通过Smad依赖性信号传导的肿瘤抑制因子。在疾病的后期阶段，TGF β信号传导部分地在致癌Ras的影响下转换为肿瘤促进。具体目的是1）检验组蛋白脱乙酰酶是Smad结合伴侣和Smad依赖性信号传导的调节剂的假设; 2）使用微阵列分析检验TGF β在Ras转化的细胞中诱导独特转录组的假设，然后使用结果进一步表征TGF β作为肿瘤促进剂; 3）使用TGF β信号传导增强的基因工程小鼠，在TGF β信号传导和结直肠癌的动物模型中测试TGF β具有肿瘤抑制和肿瘤促进功能的假设。剖析TGF β的肿瘤抑制作用与肿瘤促进作用中涉及的途径将导致选择性抑制其不期望的作用而不损害其肿瘤抑制功能的机会。