原癌基因ras家族蛋白Rab43的结构、功能与调控研究

原癌基因ras超家族控制细胞的生存、发育、迁移等各项活动，在整个胞内信号传导网络中起到承上启下的枢纽作用。Rab43作为Ras超家族的代表性成员，是维持高尔基体稳定性的关键因子，也是胞内物质的膜运输途径的重要分子开关。Rab43及其调控蛋白的异常与多种癌症的发生发展密切相关。由于胞内生物过程极其复杂，Rab43明确的功能与调控机制尚无定论，严重制约人们了对相关疾病的病理理解与靶向药物研发。本研究拟针对Rab43及其负调控蛋白RN-tre的调控机制，结合蛋白结构、酶动力学、细胞实验等技术探索Rab43结构与功能之间的关系、RN-tre与Rab43的特异性相互作用，以及突变体Rab43与RN-tre造成各种疾病的分子原理。从而使人类进一步认识Ras超家族参与的信号传递途径；了解胞内膜运输过程；完善胞内对于Ras超家族成员相关通路的调控模型；并为针对性的靶向药物研发奠定基础，提供科学依据。

The oncogenic Ras superfamily plays a critical role in the cell signaling network and controls survival, proliferation and migration of the whole cell. Rab43 is one of the most important members of Ras superfamily, by which it maintains a functional Golgi complex and switches between the on and off states to control the intracellular membrane trafficking process. Abnormal Rab43 and its regulatory proteins are associated with multiple types of cancer. Due to the complicated biological process and regulation Rab43 involved, it is not established yet how Rab43 can perform the unique function using its structure, and how Rab43 is specifically regulated and deactivated. The lack of these knowledge severely delays the study of relative diseases and drug discovery. In this study, we propose to focus on Rab43 and its negative regulator RN-tre, by investigating the structure-function relationship of Rab43, the specific interaction between Rab43 and RN-tre as well as the molecular mechanism of diseases caused by abnormal Rab43/RN-tre. And by integrating multiple approaches including structural, biochemical and kinetic method, this research will expand the knowledge of Ras superfamily mediated signaling cascade, provide mechanistic insights into the intracellular membrane trafficking, benefit the overall regulatory model for the Ras superfamily, and finally shed light on the related targeted drug discoveries.