TGF-Beta Regulation of Intestinal Epithelial Cells

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的决定性改善。因此，继续研究结肠癌的分子发病机制，以提高诊断和治疗水平是至关重要的。在过去的十年里，我们研究了自分泌生长抑制因子转化生长因子β (tgfβ)在正常和异常肠上皮生长中的作用。在此期间，TGFbet及其受体和Smad信号通路已被确定为肠上皮肿瘤抑制的关键轴。然而，在某些情况下，tgf - β信号可能有助于肿瘤促进，这一双重功能在肿瘤疾病中得到越来越多的认识。我们建议在体内和体外肠道肿瘤模型中探索TGFbeta的双重活性，特别是在致癌Ras的背景下，我们已经将其定义为生长抑制性smad依赖性TGFbeta信号传导的关键抑制因子。总体假设是tgfβ在肿瘤发生早期通过smad依赖性信号传导成为肿瘤抑制因子。在疾病的后期，tgf - β信号在部分致癌Ras的影响下转换为肿瘤促进。具体目的是：1)验证组蛋白去乙酰化酶是smad结合伙伴和smad依赖信号的调节剂的假设；2)利用微阵列分析验证TGFbeta在ras转化细胞中诱导独特转录组的假设，然后利用结果进一步表征TGFbeta作为肿瘤启动子的特性；3)利用TGFbeta信号增强的基因工程小鼠，在TGFbeta信号和结直肠癌动物模型中验证TGFbeta同时具有抑瘤和促瘤功能的假设。对TGFbeta的肿瘤抑制与肿瘤促进作用的通路进行解剖，将有机会选择性地抑制其不良作用，而不损害其肿瘤抑制功能。

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.