自噬是溶酶体依赖的亚细胞降解途径，在清除废物、提供能量以及维持细胞内环境稳定中起重要作用。核孤儿受体TR3/Nur77可作为转录因子结合到DNA应答元件激活下游靶基因转录；还可在凋亡剂刺激下转运到线粒体诱导肿瘤细胞凋亡。TR3/Nur77的体内配体尚未发现，这极大限制了对其生理功能的深入研究。我们多年来致力于TR3/Nur77新功能的研究，并发现了首个TR3/Nur77激动剂。最近，我们发现一类化合物能够诱导TR3/Nur77的线粒体转运，并通过自噬途径抑制肿瘤细胞生长。但其诱导自噬的分子机制和生理意义仍有待于研究。为此，本课题拟：1）通过作用机理和信号通路研究，阐明TR3/Nur77诱导细胞自噬的功能作用。2）利用化合物诱导自噬的独特模型，通过蛋白质组学分析，发现参与自噬调控的新蛋白，开展相关的机制和通路研究。3）分析化合物通过自噬抑制肿瘤生长的构效关系，为临床治疗提供重要的先导化合物。

Autophagy, a lysosome-dependent subcelluar degradation process, plays important roles in waste removal, energy providing and intracellular environment maintaining. Orphan nuclear receptor TR3/Nur77 is a member of the steroid/thyroid receptor family. As a transcription factor, TR3/Nur77 induces the expression of many growth-related genes through targeting to the response elements on their promoter. In addition, upon certain apoptotic stimuli, TR3/Nur77 translocates from the nucleus to the mitochondria, and initiates cell apoptosis. However, no physiological ligand for TR3 has yet been identified, which blocks our deeply study on physiological functions of TR3/Nur77. We have focused on the biological functions of TR3/Nur77 for several years, and identified Csn-B, the first agonist of TR3/Nur77. Recently, we found some Csn-B analogues can induce TR3/Nur77 mitochondrial targeting, consequently inhibit the growth of tumor cells through autophagy pathway. However, how TR3 involves in the regulation of autophagic cell death in tumors and its regulatory signaling pathways are still unknown. In this project, we will: 1) explore the functional mechanism of TR3/Nur77 in autophagy and related regulatory pathways; 2) identify novel proteins involved in autophagy through analysis of proteomics using unique model of compounds; 3) analyze the structure-activity relationship of compounds that inhibit tumor growth via autophagy pathway. We believe that our study will not only reveal a novel function of TR3 on autophagic cell death, but also provide a new strategy and a unique lead compound for tumor therapy.