体内抑制LRP16基因调控脂联素和胰岛素抵抗的作用及机制研究

项目名称： 体内抑制LRP16基因调控脂联素和胰岛素抵抗的作用及机制研究

项目编号： No.81471026

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王安平

作者单位： 中国人民解放军总医院

项目金额： 75万元

中文摘要： 糖尿病已成为日益严峻的公共健康问题，胰岛素抵抗（IR）是大多数T2DM启动、进展要素，研究如何改善体内IR及作用机制对最终预防T2DM 的发生发展甚为重要。白血病相关蛋白16（LRP16）是我们课题组首先克隆鉴定的与雌激素肿瘤紧密相关并逐渐被发现与炎症、代谢也可能相关的基因。我们近来系列研究发现LRP16在细胞中可导致 IR发生，但机制未明。脂联素是公认与IR关系最为紧密的特异性细胞因子，我们前期体外实验结果提示LRP16对脂联素具有负向调节作用，然而LRP16在体内对脂联素和IR的作用及调控机制尚不清楚。本课题主要在体内研究LRP16对脂联素及IR的调节作用及分子机制，通过条件性LRP16基因敲除和腺病毒介导基因抑制模型在体内探讨抑制LRP16增强脂联素功能和缓解IR的作用及机制。为寻找体内有效缓解IR的潜在靶分子并阐明调控机理做出新突破，进一步拓展糖尿病防治的新靶点和新思路。

中文关键词： 白血病相关蛋白16；胰岛素抵抗；脂联素；条件性LRP16基因敲除

英文摘要： Diabetes is increasing at an alarming rate and has become a serious public health problem worldwide. Insulin resistance (IR) is an essential causal factor for the development of type 2 diabetes (T2DM). Therefore,understanding the in vivo mechanisms underlying IR is essential for the treatment and ultimate prevention of T2DM. Leukemia-related protein 16 (LRP16) is a gene first cloned and characterized by our group. LRP16 is tightly associated with estrogen-induced tumors and might also be involved in inflammation and metabolism regulation. We have conducted a series of studies showing that LRP16 contributes to IR in cell lines in vitro, but the mechanism remains unclear. Adiponectin is a well-recognized specific cytokine highly correlated with IR. Our preliminary data indicate that LPR16 negatively regulates adiponectin functions whereas the effects of LRP16 on adiponectin functions and IR in vivo and their underlying mechanisms remain largely unknown. Our proposed study aims to investigate the molecular mechanisms underlying the role of LRP16 in regulating adiponectin functions and IR in vivo. We will study whether suppression of LRP16 in vivo can facilitate adiponectin functions and ameliorate IR using LRP16 conditional knock-out mouse models and adenovirus-mediated suppression of LRP16 expression in mice. Our work will make an important breakthrough in elucidation of IR mechanisms in vivo and seeking potential drug targets to treat IR, thus providing novel targets and directions for T2DM treatment and prevention.

英文关键词： Leukemia-related protein 16;Insulin resistance;Adiponectin;LRP16 conditional knock-out model