库欣病是严重影响生活质量的罕见病，其治疗主要依赖于手术，药物疗效不佳，故对无法实施手术的患者构成了严重威胁。睾丸孤核受体4（TR4）是近年来发现的库欣病潜在治疗靶点，但目前缺乏有效的TR4抑制剂。前期工作中我们发现抗癌药物bexarotene可能通过减少核定位TR4抑制TR4功能，从而抑制TR4下游POMC表达及ACTH分泌，对库欣病具有潜在的治疗作用。本课题拟在此基础上从分子、细胞及整体动物水平综合评价bexarotene对库欣病的疗效，通过研究bexarotene对：①核定位信号或核输出信号介导的TR4亚细胞分布、②TR4与共调节因子相互作用、③TR4与其应答原件相互结合等的影响，阐明bexarotene靶向调控TR4抑制其功能从而治疗库欣病的具体机制。此项研究的顺利完成将为bexarotene应用于库欣病的治疗奠定理论基础，并为库欣病药物的开发提供新思路。

Cushing’s disease (CD) represents one kind of rare diseases which seriously affect the life quality of patients. Its treatment depends mainly on surgery and drug efficacy is very poor, thus it is a big threat to patients who can not undergo surgery. The testicular nuclear receptor 4 (TR4) was identified to be a new target for treatment of CD in recent years, however, TR4 lacks effective inhibitors currently. Our previous study revealed that bexarotene could inhibit TR4 via decreasing the TR4 nuclear localization, and lead to inhibition of its downstream POMC expression and ACTH secretion, indicating its potential roles in treatment of CD. Our study aims to make a comprehensive evaluation of bexarotene for treatment of CD, and to clarify the detailed mechanism of targeted suppression of TR4 by bexarotene via investigating the influence of bexarotene on: (1) the TR4 subcellular distribution mediated by the nuclear localization signal or nuclear export signals; (2) the interaction between TR4 and co-regulators; (3) the affinity of TR4 to its response element. This study will provide theoretical guidance and experimental basis for the application of bexarotene in treatment of CD, and provide guidance for the development of novel CD drugs.