全氟化合物通过组蛋白乙酰化酶抑制干扰雌激素受体介导信号通路的理论研究

项目名称： 全氟化合物通过组蛋白乙酰化酶抑制干扰雌激素受体介导信号通路的理论研究

项目编号： No.21277164

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 环境科学、安全科学

项目作者： 张爱茜

作者单位： 中国科学院生态环境研究中心

项目金额： 85万元

中文摘要： 组蛋白乙酰化为表观遗传学修饰的一种重要形式，全氟化合物可通过组蛋白去乙酰化酶抑制等非配体依赖受体激活作用干扰雌激素受体介导信号通路。本项目拟采用理论模拟与实验验证相结合的研究方法，重点开展污染物引发的蛋白乙酰化水平变化对雌激素受体活化作用影响的生物化学机制研究。通过同源模建构建典型组蛋白去乙酰化酶结构，基于量子力学与分子动力学相结合的方法寻找污染物与酶可能的结合模式，模拟分析疏水活性作用通道对酶活性的调控过程，揭示全氟化合物的酶选择性抑制分子基础。将全氟化合物蛋白乙酰化水平干扰活性与其对雌激素受体信号作用通路的扰动相互关联，基于不同靶点间程序调控模式进行数学建模，诠释污染物雌激素效应的关键毒性作用路径。以计算结果指导实验研究，阐明污染物引发的蛋白乙酰化水平变化对雌激素受体活化作用影响的生物化学机制，为科学评价污染物的环境危害与健康风险提供理论依据与方法贮备。

中文关键词： 全氟化合物；组蛋白去乙酰化酶抑制；雌激素受体介导信号通路；短链脂肪酸；理论模拟

英文摘要： Disruption of intracellular estrogen receptor-mediated signaling via non receptor binding mechanism such as histone deacetylase inhibition play an important role for perfluorinated chemicals. In the present project, both theoretical simulation methods and necessary bioassays are adopted to explore disruption mechanism of estrogen receptor activity through histone deacetylase inhibition by perfluorinated chemicals. Specifically, homology modeling and function analysis of selected histone deacetylase will be performed to obtain the 3D-structure of the enzyme proteins, while quantum mechanics will be coupled with optimized molecular dynamics strategy to evaluate possible modes of action and reveal the inhibition mechanism involving the continuous open-close motion regulation of the acetyl-releasing channel door. Subsequently, molecular basis of histone deacetylase inhibition selectivity will be elucidated for typical perfluorinated chemicals. Furthermore, causality between estrogenic effect of pollutants and perturbation of estrogen receptor-mediated signaling induced by pathway components such as histone deacetylase and its substrate was explored to find the key toxicity pathway on the basis of estrogen receptor progressive activation. Finally, disruption mechanism of estrogen receptor activity through histone dea

英文关键词： perfluorinated compounds；histone deacetylase inhibition；estrogen receptor-mediated signaling；short-chain fatty acid；theoretical simulation