核受体Nur77和TGFβ信号的交互作用在结肠癌中对ID1表达的调节及机制

核受体Nur77和细胞信号TGFβ具有极其重要的生理和病理功能，但是它们之间的交互作用及其机制还不甚清楚。我们的前期研究揭示，在结肠癌细胞中Nur77和TGFβ信号存在交互作用，并产生对癌基因ID1表达的精致调节。据此，本项目将在分子、细胞和动物水平上，用多学科交叉的方法研究Nur77和TGFβ信号在转录水平和翻译后水平对ID1表达的调节作用，以及Nur77和TGFβ在调节ID1表达中所产生的交互作用及交互机制；研究Nur77和TGFβ交互调节ID1同结肠癌发生发展的关联，以及Nur77配体对此交互作用的调节和由此产生的结肠癌干预手段。本项目的开展将揭示Nur77和TGFβ信号的交互作用产生了对ID1表达的双层、双重和双向的调节模式，展现了机体内一种精致的核受体和细胞信号之间的交互作用；本项目还将揭示一个新的基于Nur77和TGFβ交互作用的结肠癌病理机制和治疗手段。

Both nuclear receptor Nur77 and TGFβ signaling pathway play pivotal roles in a plethora of biological and pathological processes. However, their crosstalk and the underlying mechanism and activity are not clear. Our preliminary results indicate that Nur77 and TGFβ signaling have intricate crosstalk, leading to the delicate regulation of the expression of inhibitor of differentiation 1 (ID1) in colon cancers..Our objectives of this proposal are to define the molecular modes and mechanisms of Nur77 and TGFβ signaling in reciprocal regulation of ID1 expression, and to reveal the correlation of the reciprocal interaction and colon cancer development. Thus, in this proposed study we will apply integrated multidisciplinary approaches to explore these questions: 1) the regulatory effects of Nur77 and TGFβ on ID1 expression on both transcriptional and post-translational levels in colon cancer cells; 2) the molecular mechanisms of Nur77 and TGFβ signaling on regulation of ID1 expression on both transcriptional and post-translational levels; 3) the interaction of Nur77 and TGFβ signaling in regulating ID1 expression and the underlying mechanism; 4) the correlation of the interaction of Nur77 and TGFβ signaling in ID1 regulation and the development of colon cancers; 5) the interference of the interaction of Nur77 and TGFβ signaling in ID1 regulation by Nur77 ligands and the interference-based therapeutic approaches for colon cancers..Thus, results from our project will provide a highly integrated and delicate crosstalk between Nur77 and TGFβ signaling, presenting an unidentified regulating mode of nuclear receptor and cell signaling in the body. Our project will also reveal the novel mechanisms of the reciprocal effect of Nur77 and TGFβ signaling in ID1 regulation as well as the underlying pathological relevance to colon cancer development. Moreover, the potential therapeutic approaches and lead compounds on colon cancers based on the crosstalk will be revealed by our study as well.