Tph1在CREB调控胰岛β细胞功能中的作用研究

胰岛功能缺陷是2型糖尿病发病的重要环节，近年研究发现色氨酸羟化酶1（Tph1）在妊娠诱导的胰岛功能代偿中起重要作用。本课题组前期研究发现胰岛β细胞过表达Tph1显著促进胰岛素分泌；cAMP和钙信号能协同上调大鼠胰岛Tph1表达。另外，GLP-1长效类似物Exendin-4葡萄糖依赖性地增加Tph1表达。已有文献报道，cAMP和钙信号可通过刺激cAMP反应元件结合蛋白（CREB）磷酸化以及其转录共激活因子（CRTC）去磷酸化的双重机制促进CREB下游靶基因的转录，本研究拟用多种信号通路活性调节剂、慢病毒转染、报告基因、ChIP、胰岛β细胞特异性Tph1转基因和基因敲除鼠模型，探索cAMP和钙信号协同调节胰岛Tph1表达的分子机制以及Tph1作为CREB的靶基因和GLP-1类似物作用靶点的可能性，最终为寻求具有胰岛β细胞保护作用的2型糖尿病治疗药物提供理论依据。

Pancreatic β-cell dysfunction plays an important role in the development of type 2 diabetes. It has been demonstrated that tryptophan hydroxylase 1(Tph1) plays a key role in pregnancy-induced pancreatic β-cell functional adaptation. Our previous data showed that Tph1 overexpression in rat islets significantly potentiated glucose-stimulated insulin secretion. cAMP and calcium signals synergistically triggered Tph1 expression in rat islets. In addition, Exendin-4, a long-term analog of glucagon-like peptide 1, increased Tph1 expression in a glucose-dependent manner. It has been reported that cAMP and calcium can increase the transcriptional activity of CREB by inducing CREB phosphorylation and CRTC de-phosphorylation. In this study, we will use various activators and inhibitors of signal pathways, lenti-virus, reporter gene, ChIP, β-cell specific Tph1 transgenic rats and knockout mice to explore the mechanisms underlying cAMP and calcium-induced Tph1 expression, and the possible role of Tph1 as the target gene for CREB and GLP-1 analogues. This will provide possible therapeutic targets for type 2 diabetes.