Hedgehog通路在血液湍流促内皮功能紊乱中的机制研究

项目名称： Hedgehog通路在血液湍流促内皮功能紊乱中的机制研究

项目编号： No.81500345

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 姚秦钰

作者单位： 西安交通大学

项目金额： 18万元

中文摘要： Hedgehog信号通路的激活依赖于初级纤毛，且初级纤毛多分布于动脉粥样硬化易发的湍流区域。预实验结果表明，该通路是血流剪应力的应答通路。因此我们推测：Hedgehog通路可能介导湍流引起的内皮细胞功能紊乱。本研究拟（1）利用离体的湍流剪应力模型，探讨内皮初级纤毛在该通路激活中的重要作用和分子机制；（2）采用流式细胞仪技术分析该通路是否具备介导内皮细胞功能紊乱的特性，包括增殖和凋亡；(3)阐明该通路促内皮细胞功能紊乱的分子机制；（4）在与血流剪应力相关的ApoE-/-小鼠动脉粥样硬化模型中，检测该通路成员的表达情况以及其对病变的影响。本研究将为血流剪应力相关疾病的发生和发展，如动脉粥样硬化等，提供新的理论基础和研究方向。

中文关键词： 湍流剪应力；Hedgehog蛋白；初级纤毛；内皮功能紊乱；动脉粥样硬化

英文摘要： Activation of Hedgehog signaling pathway is depended on primary cilia, while athero-prone region exhibiting oscillatory shear stress (OSS) is rich in primary cilia. Our preliminary data shows that Hedgehog signaling pathway in endothelial cells is responsive to OSS. Hence, the guiding hypothesis is that OSS-regulated endothelial dysfunctions are mediated by Hedgehog. To test our hypothesis, three specific aims are proposed: (1) to study the molecular mechanism by which primary cilia regulates the OSS-activated Hedgehog pathway in vitro; (2) to examine the role of endothelial Hedgehog pathway on OSS-promoted endothelial dysfunctions, such as proliferation and apoptosis; (3) to elucidate the involvement of Hedgehog in these two above mentioned processes ; (4) to validate the participation of Hedgehog in atherosclerosis model of ApoE-/- mouse. Results from this study will establish a framework to understand the mechano-molecular basis of shear stress-related disease, such as atherosclerosis.

英文关键词： Oscillatory shear stress;Hedgehog protein;Primary cilia;Endothelial dysfunctions;Atherosclerosis