结节性硬化症（TSC）是一种常染色体显性遗传病，其临床特征为全身各器官的多发性良性肿瘤。TSC1或TSC2基因突变失活所导致的哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）过度活化是其发病的主要原因。因此，mTORC1的特异性抑制剂rapamycin被认为是治疗TSC的理想药物，但其临床试验效果并不是十分理想。我们前期研究发现，Tsc2缺失的细胞对维甲酸（RA）的敏感性显著增强；联合应用RA和rapamycin对Tsc2缺失细胞的增殖有更好的抑制作用。这些发现无疑预示着RA具有成为TSC治疗药物的前景。因此，本研究将在前期工作基础上，明确RA对Tsc1或Tsc2缺失细胞的增殖和分化的作用及相关机制，并借助小鼠模型进一步研究RA以及RA联合rapamycin对TSC的治疗作用，为TSC的治疗提供新的方法。

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, characterized by formation of benign tumors in multiple organs, including skin, brain, kidney and etc. Hyperactivation of mammalian target of rapamycin complex 1(mTORC1),caused by loss-of-function mutations of either TSC1 or TSC2, is considered to be the leading cause of benign tumor formation in TSC disease. Therefore, rapamycin,the mTORC1 specific inhibitor, is believed to be an efficient drug for TSC. However, it does not perform very successfully in clinical trial. Our previous studies indicated that the Tsc2 deficient cells exhibit significantly increased sensitivity to retinoic acid (RA); and the combination of RA and rapamycin demonstrates a synthetic inhibitory effect on the proliferation of the Tsc2-null cells. All these preliminary data suggest that RA may be a promising drug for TSC disease. In this study, based on our previous work, we plan to clarify the roles and mechanisms of RA in the proliferation and differentiation of Tsc1 or Tsc2 deficient cells. Moreover, we also plan to explore the therapeutic effects of RA and the synthetic effect of RA and rapamycin on TSC by using several mouse models. Our studies will help understand the clinical significance of rapamycin and RA and provide new therapeutic method for TSC treatment.