血红素对胰岛素敏感性的调控作用和分子机制研究

项目名称： 血红素对胰岛素敏感性的调控作用和分子机制研究

项目编号： No.31470768

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 翟琦巍

作者单位： 中国科学院上海生命科学研究院

项目金额： 85万元

中文摘要： 胰岛素抵抗是2型糖尿病的主要特征。人群研究显示血红素摄入量与胰岛素抵抗和2型糖尿病呈正相关，但血红素对胰岛素敏感性的调控作用和机制还不太清楚。血红素可作为蛋白的辅因子参与运载氧、传递电子等并可感应氧气等气体。最近研究发现血红素还可与蛋白可逆结合而调控其生物学功能。本项目拟首先在细胞和小鼠水平研究血红素对胰岛素抵抗的诱导作用。其次，根据氨基酸序列特征和多肽与血红素的结合实验，分析和筛选可能与血红素结合的胰岛素敏感性调控蛋白。接着，通过原核和真核表达纯化候选蛋白并进行比色和质谱分析等，验证与血红素的结合。对于找到的血红素结合蛋白，研究血红素对其调控作用并探索相关分子机制。最后，在细胞和动物水平，通过过表达或siRNA调节蛋白水平，研究血红素诱导的胰岛素抵抗是否由某个特定的血红素结合蛋白所介导。本项目的开展将揭示血红素对胰岛素抵抗的诱导作用和相关分子机制，为胰岛素抵抗相关疾病的防治提供新的思路。

中文关键词： 血红素；血红素结合蛋白；胰岛素敏感性；分子机制

英文摘要： Insulin resistance is a major feature of type 2 diabetes. It has been reported that the uptake of heme is positively correlated with type 2 diabetes, but the effect of heme on insulin sensitivity and the underlying mechanisms are still unclear. Heme is an important cofactor for oxygen transport, respiratory electron transport and so on, and is also a sensor of gases such as oxygen. Recently, heme has been shown to reversibly bind with some proteins to regulate their biological functions. In this study, first, we will investigate whether heme can induce insulin resistance at cellular and animal levels. Second, we will analyze and screen potential heme binding proteins from proteins correlated with insulin sensitivity, according to the feature of heme binding motif and the binding assay for heme and the synthetic peptides. Subsequently, for the validated peptides, the corresponding proteins will be expressed and purified from prokaryotic and eukaryotic systems, and their binding with heme will be confirmed by specific light absorption and LC/MS. Then, the effect of heme on these heme binding proteins and the underlying molecular mechanisms will be investigated. Finally, the heme binding proteins will be overexpressed or knocked down by siRNA to investigate whether a specific heme binding protein mediates the effect of heme on insulin sensitivity at both cellular and animal levels. If this project can be approved, we will elucidate the effect of heme on insulin sensitivity and the related molecular mechanisms, which will provide new clues for preventing and treating insulin resistance related diseases.

英文关键词： heme;heme binding protein;insulin sensitivity;molecular mechanisms