扰流诱导内皮细胞异常增殖和炎症反应的表观遗传机制- - DNA甲基转移酶的作用

项目名称： 扰流诱导内皮细胞异常增殖和炎症反应的表观遗传机制- - DNA甲基转移酶的作用

项目编号： No.81470590

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： 周菁

作者单位： 北京大学

项目金额： 75万元

中文摘要： 血液动力学的重要因素- - 剪应力，在血管内皮细胞功能以及动脉粥样硬化发生过程中具关键作用。申请人及其合作者在近年的研究中发现，微小RNA和组蛋白去乙酰化酶等表观遗传调控因子，介导了促动脉硬化发生血液扰流产生的振荡剪力诱导的内皮细胞功能紊乱。在最近的研究中，我们又发现另外一个重要的表观遗传调控因子，DNA甲基转移酶1（DNMT1），在内皮细胞中被振荡剪力上调；DNMT1抑制后能削弱振荡剪力引起的DNA异常甲基化、增殖、和炎症反应。我们推测：振荡剪力激活DNMT1，导致全基因组DNA异常甲基化，从而改变内皮细胞基因表达和血管生理稳态。本研究将探讨1）不同类型剪力以DNMT1介导的基因组DNA甲基化谱；2）促动脉硬化发生的振荡剪力激活DNMT1的分子机制及其功能； 3）利用动物血流扰流模型和动脉硬化模型验证DNMT1的血管病生理学意义。研究结果将增进关于机械生物信号转导机制及动脉硬化发生机制的了解

中文关键词： 内皮细胞；剪应力；动脉粥样硬化；DNA甲基化；DNA甲基转移酶

英文摘要： Shear stress, the tangential component of the hemodynamic forces acting on the vascular wall, has been shown to play crucial roles in the regulation of vascular endothelial function, as well as the formation and progression of atherosclerosis. Previous studies by us, our collaborators, and others have elucidated that atheroprone shear stress modulates dysfunction of vascular endothelial cells (ECs), including aberrant proliferation, inflammation, migration, increased permeability, and releasing of some pro-atherogenic molecules, by the mediation of several molecules and factors, e.g. microRNAs and histone deacetylases (HDACs), which are epigenetic mediators regulating gene expression without altering the underlying DNA sequences. One of the most important molecules that have been found in our recent study is another epigenetic mediator, DNA methyltransferase 1 (DNMT1), whose expression and activation could be induced by atheroprone oscillatory shear stress (OS) in ECs and its pharmacological inhibition attenuated OS-induced DNA hypermethylaion, proliferation, and inflammatory responses of ECs. With the new finding, we hypothesize that DNMT1 governs the effects of OS on endothelial functions and atheroma formation. Through the activation of upstream mechanotransduction, signaling and regulatory pathways, e.g. integrins, mTOR, and TLRs, OS-induced DNMT1 methylates DNA both globally and at specific loci, resulting in the changes of gene expressions and functional consequences. Three specific aims are proposed to test the guiding hypothesis. Aim 1 will profile the DNMT1-mediated genome-wide DNA methylation patterns in ECs in response to OS versus atheroprotective pulsatile shear stress (PS). Aim 2 will elucidate the regulatory pathways and functional consequences that involved in or resulted from the activation of DNMT1 by OS. Aim 3 will validate the roles of DNMT1 in endothelial functions and atherogenesis in vivo. The results from the present study will help to identify the hitherto poorly understood connection between DNA methylation and atheroprone hemodynamic forces applied to the vascular endothelium and to discover new target biomarkers highly associated with the translational and clinical medicine research with great potentials for biotechnological development, thereby facilitating the development of new therapeutic strategies for the disease.

英文关键词： Endothelium;Shear stress;Atherosclerosis;DNA methylation;DNMT1