JAZF1在胰岛素抵抗的发生和发展中作用机制的研究

Recent reports have shown that JAZF1 is associated with T2DM, prostate cancer and mesenchymal neoplasm in endometrium. In the previous study, we found that JAZF1 led to a reduction of lipogenesis and an increase of lipoclasis in 3T3L1 cell. In JAZF1-Tg/+ mice,overexpression of JAZF1 resulted in a decrease of CREB and TORC2 expression essayed by gene chips. High fat feeding in these mice led to lower body weight, blood glucose and fat levels compared with control mice.In this study, we'll want to bulid a JAZF1-Tg/- mice fed high fat diet (HFD), for the combination of genetic and environmental factors, to obtain a model of insulin resistance. In this model, insulin sensitivity is examined by extensive euglycemic- hyperinsulinemic clamps with [3H-3]-glucose as a tracer.In addition, the glucose and lipid metabolism as well as insulin signal pathway were also investigated for exploring the effects of JAZF on these changes. This study will identify both the central nervous system and peripheral issues as a potentially important target for the beneficial effects of JAZF1 in the treatment of diabetes and obesity.

近年的研究表明JAZF1与2型糖尿病和肥胖以及前列腺癌、子宫内膜间质肿瘤具有密切的相关性。我们在前期工作中发现JAZF1导致细胞脂质合成减少，脂解增强；随后制备了JAZF1-Tg/+小鼠模型。基因芯片表达谱差异分析并验证JAZF1表达增高时，CREB及TORC2表达水平下降；高脂喂养后该小鼠体重，血糖、血脂水平较野生鼠偏低。本研究拟构建JAZF1-Tg/-小鼠，予高脂饲养，使其同时具备遗传和环境因素的共同作用，打造更具胰岛素抵抗（IR）表型的小鼠模型。随后，用扩展胰岛素钳夹术探讨模型小鼠胰岛素敏感性变化，并从中枢和外周全面探讨JAZF1过表达及表达低减时糖、脂代谢和胰岛素信号系统的变化。初步勾勒出在JAZF1基因缺陷和环境因素共同作用的特定条件下，糖、脂代谢紊乱和胰岛素信号调控网络变化及可能的作用机制。从而为寻找IR发生的分子生物学靶点提供极有价值的数据和资料，同时也为其治疗提供新的靶点。

JAZF1 （juxtaposed with another zinc finger gene 1，与另一个锌指并列的基因1）又名Tip27（TAK1-interacting protein 27，与TAK1相作用的蛋白27）。近年的研究表明JAZF1与2型糖尿病和肥胖以及前列腺癌、子宫内膜间质肿瘤具有密切的相关性。我们在前期工作中发现JAZF1导致细胞脂质合成减少，脂解增强；随后制备了JAZF1-Tg/+小鼠模型。课题组进行JAZF1/Tip27过表达转基因小鼠的制备，杂交，鉴定等，获得纯合子JAZF1过表达转基因小鼠。探讨JAZF1基因上调对糖、脂代谢及胰岛素信号系统的变化。完成小鼠组织细胞基因表达和胰岛素信号分子的测定。研究JAZF1基因对肝脏脂肪酸合成，肝细胞脂质累积的影响。双荧光素酶报告基因分析JAZF1对脂肪酸诱导的肝细胞内脂质累积的关键因子SREBP-1C的调控。研究JAZF1基因在中枢上调对基础代谢及肝脏糖代谢的影响。