2型糖尿病大鼠胰岛星状细胞的生物学特性及其活化机制

胰岛纤维化是导致2型糖尿病（T2DM）胰岛β细胞功能进行性减退直至衰竭的重要病理生理机制之一。本课题组在研究胰岛纤维化细胞机制的过程中意外观察到GK大鼠纤维化胰岛内存在异常活化的星状细胞，它具有极强的致纤维化作用，且明显抑制胰岛β细胞功能。这促发我们进一步认清该胰岛星状细胞（ISC）的生物学特征，阐明导致其高度活化的内在分子机制，从而找到阻断其活化的关键靶点，对阻止甚至逆转胰岛纤维化和β细胞功能衰退意义重大。本研究拟从体内、体外两个水平运用ISC分离、高通量测序、蛋白质芯片、免疫荧光、real time PCR、western blot、基因转染等技术比较T2DM及其对照动物ISC生物学特性；描绘T2DM不同病程ISC的基因谱和蛋白谱；探寻触发其异常活化的关键分子；分析关键分子在ISC致胰岛纤维化和β细胞功能衰退中的作用，从而为防治T2DM提供新的理论依据和作用靶点。

Islet fibrosis is one of the major pathological changes in type 2 diabetes mellitus(T2DM)which contributes to the progressive decline and even failure of pancreatic β-cells. In our previous study on the cellular mechanism of islet fibrosis, we unexpectedly observed a highly activated stellate cells in the fibrotic islet of GK rat,which contribute to fibrogenesis and significantly inhibit β-cell function. This stimulates us to explore the biological characteristics of the islet stellate cells (ISC), clarify the intrinsic molecular trigger of highly activation. That will be a great significance for prevention or even reversal of islet fibrosis and β-cell loss.In this project, we want to compare the biological characteristics of ISC from T2DM animal with control; draw the gene and protein profile of the ISC at different pathological stage of T2DM; explore the key molecules for ISC activation; and analysis the effects of such factors on ISC induced islet fibrosis and β-cell dysfunction by ISC separation, high-throughput gene chip, protein chip, immunofluorescence, real time PCR, western blot, and gene transfection techniques. Eventually,this study will provide a new theory and novel treatment target for T2DM.