tRXRα调控非可控性炎症恶性转化网络的关键节点作用及新型调控机制研究

With the funding from the National Natural Science Foundation, we have made significant advance in the understanding of the role of tRXRα, an N-terminally truncated retinoid X receptor-alpha (RXRα) produced in tumor cells, in the control of the development of chronic inflammation and cancer and the underlying molecular mechanisms. We discovered recently that tRXRα could mediate NF-κB activation in both macrophages and cancer cells through its nongenomic actions and that nonsteroidal anti-inflammatory drug Sulindac and analogs, a class of potent anti-cancer drugs, could bind to tRXRα through a new binding mechanism, which induces tRXRα tetramerization. Based on these exciting findings, we hypothesize that tRXRα is a critical mediator of signaling network responsible for the development of tumor inflammatory microenvironment and that tRXRα tetramerization plays a crucial role in the regulation of tRXRα activities. To address our hypothesis, we propose to utilize a multiple disciplinary approach to study the role and mechanism of tRXRα regulation of NF-κB signaling pathways in macrophages and tumor cells as well as the development of tumor inflammatory microenvironment, to characterize the new binding site on the surface of tRXRα protein and its role in the promotion of tRXRα tetramerization by Sulindac and analogs, and to identify more selective Sulindac analogs for studying the role of tRXRα and its mechanism of action. Results obtained will provide new insight into the role of tRXRα in the development of chronic inflammation and cancer and new strategies for developing cancer therapeutics targeting tRXRα.

本课题组在国家自然科学基金重大研究计划资助下，在核受体突变体tRXRα调控非可控性炎症与肿瘤交互关系和作用机制方面取得了系列重要成果，开创性发现具有抗癌活性的非固醇类消炎药舒林酸及衍生物与tRXRα表面新型结合位点相互作用诱导tRXRα四聚化，调控TNFα炎症信号网络的新型作用机制。本项目在前期基础上，围绕tRXRα介导肿瘤炎症微环境产生和炎－癌转化网络的关键节点作用及其四聚化调控其功能的新型作用机制，以炎－癌转化中已有较好研究基础的舒林酸及衍生物为探针，研究tRXRα在肿瘤及炎症细胞中激活NF-κB通路及网络，促进肿瘤炎症微环境产生及非可控性炎症恶性转化的功能及机制, 阐述新型tRXRα小分子结合位点及四聚化调控tRXRα节点功能的新型作用机制, 发现tRXRα及新型调控机制的特异性调控小分子。项目将发挥多学科的特点以及交叉优势，为从炎－癌转化角度诊治肿瘤提供新的标记物和药物靶点。

本课题组在国家自然科学基金重大研究计划资助下，发挥多学科的特点以及交叉优势，研究RXRα和Nur77介导炎症－癌症转化信号通路的作用；阐述新型tRXRα小分子结合位点及四聚化调控tRXRα节点功能的新型作用机制, 发现靶向tRXRα、Nur77及新型调控机制的特异性调控小分子。项目研究首次揭示了tRXRα形成四聚化调节PI3K / Akt存活途径的非基因组作用；研究确定了通过Nur77介导的自噬从而消除损伤线粒体抑制炎症反应的新途径。以上开创性的成果为核受体非基因型功能作用机理的研究以及药物靶点的开发奠定了坚实的理论基础，探索出现实可行的研究模式。通过本项目的研究，在国际主流杂志发表包括Molecular Cell、Nature Communication在内的论文8篇，申请发明专利1项。申请后续经费3000余万。培养博士研究生 4人，硕士研究生14人。圆满的完成了研究计划。