c-Abl-肌动蛋白细胞骨架结构相关信号通路在静脉桥管衰败发生中的机制研究

Coronary artery bypass grafting (CABG) is an important method of treating coronary artery disease. As the most frequently used bypass materials, vein graft occlusion (vein graft failure) affects the long term efficacy of CABG, and its molecular mechanism remained elusive. Our previous researches and others have found that migration/proliferation/differentiation of smooth muscle progenitor cells contributes to vein graft failure after grafting. We has confirmed that non-receptor tyrosine kinase c-Abl regulate smooth muscle biological function through affecting actin cytoskeleton dynamics. Our team also found that c-Abl and its upstream/downstream signal pathways changes when smooth muscle progenitor cells differentiate into smooth muscle like cells. In this study, we will carry out the research from cells to overall level by using molecular biology techniques to reveal how c-Abl interacts with its upstream/downstream signal pathways, as well as their role in regulating actin cytoskeleton dynamics and biological function of smooth muscle progenitor cells, and to study how this interaction affects pathophysiology of vein graft failure and its molecular mechanism, so as to provide novel thoughts into molecular mechanism of vein graft failure, and find novel targets in preventing and treating vein graft failure.

冠脉搭桥手术是治疗冠心病的重要方法，而静脉桥管的远期衰败是影响搭桥手术远期效果的主要原因，但其分子机制及调控仍知之甚少。申请者与其他人的研究发现，血管平滑肌前体细胞迁移、增殖、分化是导致静脉桥管远期衰败的重要原因。我们的研究发现非受体酪氨酸蛋白激酶c-Abl调控肌动蛋白细胞骨架动态结构，且c-Abl及其上下游信号通路在平滑肌前体细胞分化前后表达水平及活性不同。因此，我们推测c-Abl调控肌动蛋白细胞骨架结构相关信号通路在调控平滑肌前体细胞生物学功能方面的具有重要作用，c-Abl可能是静脉桥管衰败发生的重要信号节点。本研究拟从细胞、动物模型和临床标本研究c-Abl与上下游信号通路的相互作用，揭示其调控平滑肌前体细胞肌动蛋白骨架结构及生物学功能的分子机制，阐明相关通路在静脉桥管衰败病理生理过程的作用，从而为静脉桥管衰败的防治提供新的思路，改善冠脉搭桥患者的长期预后。

静脉桥管的远期衰败是影响搭桥手术远期效果的主要原因。血管平滑肌前体细胞在静脉桥管远期衰败中发挥重要作用。我们的研究发现静脉桥管衰败后，非受体酪氨酸激酶c-Abl表达增加，c-Abl抑制剂imatinib通过抑制ERK1/2信号通路（TGFβ的非Smad信号通路），抑制平滑肌细胞表型转换，增殖，迁移，并减轻小鼠静脉移植再狭窄; 平滑肌细胞c-Abl信号通路相关的NLRP3缺失，可抑制Smad2/3信号通路 （TGFβ的Smad信号通路）, 减轻小鼠动静脉瘘导致的内膜增生; Imatinib介导的c-Abl抑制，可阻止平滑肌细胞凋亡，从而减少小鼠主动脉夹层的发生。TGFβ-c-Abl 信号通路参与静脉移植再狭窄的作用，为阐明静脉移植物衰败机制提供新的实验依据，为探索干预策略提供新的靶点。