ClC-3氯通道蛋白在肾上腺素能受体介导心肌肥厚中的功能研究

项目名称： ClC-3氯通道蛋白在肾上腺素能受体介导心肌肥厚中的功能研究

项目编号： No.31500926

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 李春梅

作者单位： 广东药科大学

项目金额： 20万元

中文摘要： 肾上腺素能受体激动与心肌肥厚密切相关，但机制未明确。ClC-3是容积激活性氯通道的构成分子，参与细胞容积调节。我们探索性研究发现肾上腺素下调心肌细胞ClC-3的表达，提示ClC-3很可能参与肾上腺素能受体介导的心肌肥厚。本项目拟深入研究：首先，分析临床病理标本和鼠肥厚心肌与正常心肌ClC-3表达差异，并观察恢复肥厚心肌细胞ClC-3表达对细胞体积的影响，确定ClC-3在肾上腺素能受体激动诱导心肌肥厚中的重要作用；然后，利用培养的心肌细胞和心脏ClC-3基因特异性敲除的小鼠，探讨肾上腺素能受体激动下调ClC-3表达及其下调导致容积激活性氯通道缺失和细胞容积失调的机理，明确肾上腺素能受体激动→G蛋白/AC/cAMP/PKA信号通路活化→ClC-3表达↓→容积激活性氯电流↓→细胞容积失调→心肌肥厚的分子和细胞机制。项目的实施有望为心肌肥厚的防治提供新的理论依据，也将ClC-3的功能研究拓展视野。

中文关键词： 离子通道；心肌肥厚；细胞容积；肾上腺素能受体

英文摘要： Adrenergic receptor stimulation is closely related to clinical myocardial hypertrophy, but the exact mechanism is unclear. ClC-3 has been proposed as a candidate for the volume-activated chloride channel and is involved in cell volume regulation. Our exploratory study found that adrenaline reduced ClC-3 expression in the hypertrophied cardiomyocytes, suggesting that ClC-3 is likely involved in the adrenergic receptor-mediated cardiac hypertrophy. Firstly, in this project, we will analyse the expression differences of ClC-3 between hypertrophic myocardium and normal myocardium in clinical pathology specimens and mouse models induced by adrenergic receptor stimulation, and with the observation of the effects of ClC-3 expression up-regulated in the primary hypertrophic myocardial cells on cell volume, so that we could determine the important role of ClC-3 involved in adrenoceptor stimulation-induced cardiac hypertrophy. Then, in the heart-specific ClC-3 knockout mice and primary cardiac myocyte, we’ll explore the mechanism of ClC-3 down-regulation induced by adrenergic receptor activator through G protein/AC/cAMP/PKA signaling pathway, combined with the study for ClC-3 down-regulation resulted in volume-activated chloride channel deficiency and cell volume regulation disorders, clarify the underlying molecular and cellular mechanism for ClC-3 involved in adrenoceptor stimulation-induced cardiac hypertrophy. The implementation of the project is expected to provide a new theoretical basis for the study of the mechanism of adrenoceptor stimulation-induced cardiac hypertrophy, will also extend the research of the ClC-3 chloride channel protein multifunction.

英文关键词： ion channel;myocardial hypertrophy;cell volume;adrenergic receptors