核受体Nur77/TR3在肝癌发生发展中的作用机理和防治基础研究

项目名称： 核受体Nur77/TR3在肝癌发生发展中的作用机理和防治基础研究

项目编号： No.U1405224

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 吴乔

作者单位： 厦门大学

项目金额： 256万元

中文摘要： 作为闽台高发恶性肿瘤, 肝癌在福建省癌症死亡率居所有恶性肿瘤之首。因此,探究肝癌发病机理和开展防治研究非常紧迫和意义重大。核受体Nur77/TR3在代谢、发育、细胞分化、存活和死亡以及体内稳态平衡等生理活动中发挥重要作用，是很好的药靶。我们前期研究证明Nur77/TR3作为正负调控因子参与肿瘤、糖尿病、肥胖和炎症等疾病过程。本项目首先在动物模型和临床样品中明确Nur77/TR3抑制肝癌的生物学功能和生理效应，再从细胞分子生物学入手，分析Nur77/TR3通过代谢通路抑制肝癌发生发展的作用机理，以及上游因子对Nur77/TR3功能的影响；在此基础上，根据确定的关键节点蛋白，建立独特的筛选模型，从自己建立的小分子化合物库筛选出特异靶向Nur77/TR3抑制肝癌的化合物，并在各种诱导肝癌的小鼠模型进一步验证。通过研究，阐明核受体在肝癌发生发展中的作用，为临床治疗提供重要的研究方向和先导化合物。

中文关键词： 核受体Nur77/TR3；肝癌；代谢；化合物；信号通路

英文摘要： Among the malignant tumors, hepatoma is associated with the highest mortality rate in both Fujian and Taiwan. It is of great urgency and significance to understand the mechanism of hepatomagenesis to device measures of prevention and cure. Nuclear receptor Nur77/TR3 is an important pathophysiological factor in metabolism, development, cell differentiation, proliferation and death, as well as maintaining homeostasis. It is with great potential to target Nur77/TR3 for therapy. Our previous studies have demonstrated that Nur77/TR3 can both positively and negatively regulate signal transduction pathways in tumorgenesis, diabetes, obesity, and inflammation. In this study, the biological and physiological functions of Nur77/TR3 will be probed in different mouse models and clinical samples, and the molecular mechanism of inhibition by Nur77/TR3, as well as its upstream regulatory factors, in hepatomagenesis will be investigated. Cell-based screening models will be made with key proteins identified in the study to obtain compounds specifically targeting Nut77/TR3 and blocking the development of hepatoma. These selective compounds will be further tested in different mouse models. The aim is not only to unravel regulatory mechanism of nuclear receptor in tumorgenesis but also to provide conceptual breakthrough and lead compounds for therapeutics of hepatoma.

英文关键词： NULL