氨基酸-Rab1A-mTORC1信号轴调控Pdx1蛋白磷酸化及其控制小鼠血糖稳态中的机制研究

氨基酸作为生命体组成部分和营养物质，同样因作为化学信使调控生长代谢而越来越受到重视。mTOR作为氨基酸信号通路核心分子，其调控机制目前还不清楚。我们前期基于酵母基因组筛选技术鉴定得到小分子GTP酶Rab1A，能够介导氨基酸信号活化mTOR通路。成年小鼠敲除Rab1A后血糖升高、葡萄糖耐受变差，进一步发现其根本原因在于Pdx1蛋白降低导致胰岛素转录和产生降低。在此基础上我们提出假说：氨基酸-Rab1A-mTORC1信号轴通过调控Pdx1磷酸化从而控制小鼠血糖稳态。为了验证这一假说，将在细胞水平鉴定Pdx1磷酸化位点，探索该位点与其功能、亚细胞定位、泛素化降解关系；体内实验通过饥饿与不同含量蛋白饮食等处理寻找氨基酸信号调控Pdx1磷酸化和血糖状态的体内证据。本研究将有助于理解氨基酸信号对于血糖调控作用机制，探索葡萄糖和氨基酸两大营养元素之间的网络交谈，为糖尿病发生机理和治疗提供新的视角。

AAs (Amino acids) are basic building blocks and nutrients of life. It has been increasingly appreciated that amino acids function as chemical signals to regulate growth and metabolic processes. As the master regulator of amino acids signaling, yet the regulation of mTOR remains elusive. We identified a small GTPase Rab1A by genomic screening in yeast, which functions as an mTOR activator mediating AAs signal to cell growth. The adult mice upon Rab1A knockout demonstrated elevated fasting blood glucose and worsened glucose tolerance. The underlying reason lies in the transcription and production of insulin as a result of reduced Pdx1 protein in Rab1A knockout mice. Hence, we propose to test the hypothesis that amino acids-Rab1A-mTORC1 signaling controls glucose homeostasis via regulating Pdx1 phosphorylation. We will decipher the mechanisms and significance of phosphorylation of Pdx1 by amino acids using cell line and gene-engineered mouse models. If successful, the current study will be helpful to understand how amino acids regulate glucose homeostasis and the crosstalk between glucose and amino acids providing a novel insight of diabetes etiology and therapeutics.