基于TRIB3信号转导网络的2型糖尿病药物基因组学分子靶标鉴定与功能研究

Type 2 diabetes mellitus (T2DM) is a serious disease of genetic and environmental interaction. Multiple international drug clinical study evidenced that sustained hypotensive and anti-diabetic administration was able to significantly improve the prognosis of diabetic cardiovascular disease. Recent study demonstrated that TRIB3 gene played an important role in the regulation of T2DM and its cardiovascular complications. Since we have completed the scaled drug clinical study of T2DM with 3218 cases of patients and continued follow-up for 5 years, we recently discovered that the genetic variations of SMARCD3, POLR2A, ATF6 and JUND genes affected the therapeutic effects of T2DM when treated together with gliclazide capsule, perindopril and indapamide, as well as ATF4, SSR1, CABLES1 and NAFATC1 genetic variants associated with T2DM and its complications of myocardial infarction. This project aim to verify the findings of molecular targets in the remaining samples, and further investigate the corresponding gene expression and regulation of target genes by using gene site directed mutagenesis, gene silencing, SiRNA dual fluorescence reporter gene, Western Blot technology, etc. This project will provide new scientific guidance for molecular typing of T2DM and its clinical individual prevention.

2型糖尿病(T2DM)是一类遗传和环境交互作用的重大疾病。国际大型药物临床研究发现2型糖尿病持续降压并降糖能显著改善糖尿病心血管疾病预后。最新研究发现TRIB3基因在2型糖尿病及其心血管并发症调控中起重要作用。我们前期已完成3218例2型糖尿病患者的大型药物临床研究并持续随访5年，近期在384例小样本中针对TRIB3转导网络关键基因的预实验新发现SMARCD3、POLR2A、ATF6及JUND遗传变异与格列齐特联合培哚普利+吲达帕胺治疗2型糖尿病患者的疗效相关，ATF4、SSR1、CABLES1及NAFATC1遗传变异与2型糖尿病及其心梗并发症相关。本课题旨在余下样本中完成以上新分子靶标的相关性验证，进而应用基因定点诱变、SiRNA基因沉默、双荧光报告基因、Western Blot等技术研究新位点对相应基因表达及靶基因调控的作用，为2型糖尿病的分子分型和临床个体化防治提供新的科学依据。

2型糖尿病(T2DM)是一类遗传和环境交互作用的重大疾病。国际大型药物临床研究发现2型糖尿病持续降压并降糖能显著改善糖尿病心血管疾病预后。最新研究发现TRIB3基因在2型糖尿病及其心血管并发症调控中起重要作用。我们前期已完成3218例2型糖尿病患者的大型药物临床研究并持续随访5年，近期在384例小样本中针对TRIB3转导网络关键基因的预实验新发现SMARCD3、POLR2A、ATF6及JUND遗传变异与格列齐特联合培哚普利+吲达帕胺治疗2型糖尿病患者的疗效相关，ATF4、SSR1、CABLES1及NAFATC1遗传变异与2型糖尿病及其心梗并发症相关。采用双荧光素酶报告基因等其他相关的分子生物学技术手段，在HEK-293、BxPc3等细胞系中确证TRIB3 (rs2295490)、ATF6（rs12086247）、SMARCD3（rs58125572）、RASGRP1 (rs55699464、rs7403531)、miR-3188（rs7247237）、miR-4532 (rs60452575)等基因多态性与药物疗效之间的内在机制。利用通过过表达或敲减基因等手段，研究TRIB3、SMARCD3、RASGRP1、FAF1、APOE对糖尿病发病的主要组织（如肝脏和胰岛等）相关表型（糖原摄取、脂滴形成、胰岛素释放等）及信号通路的影响。探索这些基因在药物作用过程当中所充当的作用及其信号转导途径，为2型糖尿病的分子分型和临床个体化防治提供新的科学依据。