巨噬细胞的迁移抑制是动脉粥样硬化发生发展的核心事件，氧化低密度脂蛋白（oxLDL）和血管基质硬度是其影响因素。骨架蛋白调节细胞力学性质和迁移。我们新发现，一种骨架蛋白-原肌球调节蛋白1（Tmod1）介导oxLDL和基质硬度对巨噬细胞力学性质的协同作用，且调节oxLDL受体CD36和力学感受器整合素的表达。由此提出假说：Tmod1通过促进CD36和整合素信号通路的协同作用，参与oxLDL和基质硬度联合作用对巨噬细胞力学特性的调节，加速动脉粥样硬化发生发展。我们拟利用生物力学、分子生物学技术、Tmod1-/-小鼠和高血管硬度模型小鼠，验证巨噬细胞中Tmod1对oxLDL联合基质硬度引起的细胞力学改变的影响；阐明Tmod1如何影响CD36、整合素及其通路间的协同作用；在体内验证血脂和血管硬度改变时巨噬细胞的Tmod1对动脉粥样硬化的影响。本研究将从生物力学的角度为动脉粥样硬化提供新的防治思路。

The migration inhibition is the core event in the development of atherosclerosis. Oxidized low density lipoprotein (oxLDL) and matrix stiffness of the blood vessel are two major determinants for it. The cytoskeletal proteins regulate the mechanical properties and migration of cells. Recently, we found that a cytoskeletal protein, Tropomodulin1 (Tmod1), mediated the synergistic effect of oxLDL and matrix stiffness on the macrophage mechanics. Importantly, Tmod1 was found regulate the expressions of oxLDL receptor, CD36, and the mechanosensor, integrin. Therefore, we hypothesize that Tmod1 participates the mechanical regulation of oxLDL and matrix stiffness by promoting the cooperation of CD36 and integrin signaling pathways, thus accelerates the development of atherosclerosis. To test our hypothesis, we will use biomechanical, molecular and biological techniques and utilize our Tmod1-/- mouse and a mouse model with high blood vessel stiffness. We will identify the role of Tmod1 in the mechanical alterations in macrophages caused by oxLDL and matrix stiffness. Then we will investigate how Tmod1 affects the CD36 and integrin signaling pathways and their cooperation. Finally, by manipulating the blood lipid and blood vessel stiffness in animals, we will study the role of macrophage Tmod1 in the development of atherosclerosis. This project will provide us new ideas for preventing atherosclerosis from the viewpoint of biomechanics.