核受体的活性受到其配体的特异性调节，发现和研究新型配体将揭示核受体重要的功能。我们的前期研究首次揭示了核受体RXRα的新型硝基配体 - Z化合物（Z-10和Z-12），并发现Z化合物以RXRα/tRXRα依赖的方式抑制TNFα/NFκB信号并且激活TNFα介导的肿瘤细胞凋亡。据此本课题将在分子、细胞和动物水平，用多学科交叉的方法深入研究Z化合物结合RXRα的独特方式以及其对RXRα的基因型和非基因型活性的调节；同时研究Z化合物以RXRα/tRXRα依赖的方式调节TNFα/NFκB信号以及和TNFα协同诱导肿瘤细胞凋亡的机制；并且研究Z化合物依赖RXRα/tRXRα的结构和活性优化。本课题的开展将首次展示一种新型RXRα硝基配体及其独特活性，修正RXRα配体的概念；同时揭示RXRα/tRXRα与TNFα/NFκB信号的新的相互作用方式，以及一种肿瘤发展的新机制和潜在的肿瘤治疗药物和方案。

The functions of nuclear receptors are tightly and delicately regulated by their cognate ligands, and discovering and studying novel ligands will reveal unidentified activities of nuclear receptors. Retinoid x receptor alpha (RXRα) is a unique member of nuclear receptor family and plays important and complex roles in the biological and pathological processes. We have reported N-terminally truncated RXRα (tRXRα) is able to bind the PI3K regulatory subunit p85α and promote PI3K/AKT signal activity, which is dramatically inhibited by RXRα ligands sulindac sulfide and its optimized derivative K-80003. Recently our prelimilary studies presented a novel type of RXRα ligand, the nitro-ligands - - Z compounds (Z-10 and Z-12), which bound RXRα and strongly activated RXRα transcriptional activity. Our prelimilary data also indicated that Z compounds negatively regulated TNFα/NFκB signal activity and synergistically induced cancer cell apoptosis with TNFα in a RXRα/tRXRα dependent manner. In this proposed studies, we will apply integrated multidisciplinary approaches to focuse on studying the following questions, 1) what is the mode of Z compounds binding to RXRα? 2) How do Z compounds regulate genomic and non-genomic functions of RXRα? 3) What is the molecular mechanism by which Z compounds inhibit TNFα/NFκB signal in a RXRα/tRXRα dependent manner? 4) How do Z compounds and TNFα synergistically induce cancer cell apoptosis? 5) How to optimize Z compounds in their abilities of binding RXRα and exerting RXRα/tRXRα dependent functions. The results from this research will reveal the unidentified nitro-ligands of RXRα and their unique regulations of RXRα activities, which will modify the concept of RXRα ligands. Our proposed studies will also provide a novel regulation mode of TNFα/NFκB signal mediated by RXRα/tRXRα and a mechanism of tumor development. Furthmore, the anti-cancer functions of Z compounds and their optimized derivatives may provide lead drugs and therapeutic approaches for cancer treatment.