TRPC4在内皮祖细胞增殖分化及血管损伤修复中的作用

EPCs play a key role in repairing injured blood vessels, and their capacity to repair damaged endothelium is limited. Therefore, It is important to increase the function of EPCs in the prevention early stages of the diseases induced by vascular injury such as atherosclerosis and restenosis. Previous study suggested that Ca2+ was involved to regulate the function of EPCs. In a previous study, we showed that TRPC4, the member of SOCs, may be the key in regulating EPCs Ca2+ entry,knockdown of TRPC4 signi?cantly suppressed the Ca2+ entry of EPCs. On the basis of our previous study, we hypothesized that TRPC4 affects function of EPCs by regulating its Ca2+ entry after vascular injury . To determin the effect and mechenism of EPCs proliferation，migration,differentiation induced by TRPC4 during vascular repair, we will study it by in vitro cell culture and establishment of carotid artery balloon injury model, using RNA interference, gene transfer, gene chip technology and so on, These ?ndings will provide a new mechanism for modulating proliferation，migration, differentiation of EPCs and indicate that TRPC4 may be a new target for in ducing vascular repair by EPCs ,Which will providing a theoretical basis for clinical prevention of the diseases induced by vascular injury .

内皮祖细胞(EPCs)参与损伤血管修复过程,但调控EPCs的机制不清是限制其临床应用的瓶颈。因此，深入探讨其调控机制对防治血管损伤性疾病有重要意义。研究报道EPCs的血管修复能力与钙库操纵性钙通道（SOCs）调控的钙内流有关。我们的前期研究发现，基因干扰沉默TRPC4，EPCs的钙内流明显减少。据此，本项目提出TRPC4通过调控EPCs的钙内流，影响EPCs功能的假设。通过体外细胞培养及建立颈动脉球囊损伤模型，利用RNA干扰、基因转染、基因芯片等技术，探讨TRPC4对EPCs增殖、迁移、分化的影响及其修复损伤血管能力的关系，揭示TRPC4调节EPCs功能的机制，明确TRPC4是影响EPCs血管修复能力和治疗血管损伤性疾病的新靶点，从而为血管损伤性疾病的临床防治提供理论基础。

内皮祖细胞(EPCs)参与损伤血管修复过程,但调控EPCs的机制不清是限制其临床应用的瓶颈。因此，深入探讨其调控机制对防治血管损伤性疾病有重要意义。我们的前期研究发现TRPC4及Slfn1可能参与EPCs的生物学功能的调控，为明确其影响及调控机制，本研究通过体外细胞培养，利用RNA干扰、基因转染、RNA测序等技术，探讨TRPC4及Slfn1对EPCs增殖、迁移等生物学行为的影响及其机制。结果发现：在EPCs上基因沉默TRPC4的表达,明显抑制EPCs的增殖及迁移，反之，恢复EPCs上TRPC4基因的表达，则逆转此影响。RNA 测序结果发现，HTLV-I infection 、Cytokine-cytokine receptor interaction 、herpes simplex infection 、hematopoietic cell lineage等信号通路可能参与TRPC4对EPCs的功能的调控。此外，在EPCs过表达Slfn1基因,抑制EPCs的增殖、迁移、粘附及血管环形成能力，细胞周期停滞在G1期，反之，通过RNA干扰沉默Slfn1的表达，则促进EPCs的增殖、迁移、粘附及血管环形成能力，EPCs的细胞周期进展到S期，更进一步的研究发现，过表达Slfn1基因抑制细胞周期调控基因Cyclin D1的表达，而反之则促进Cyclin D1的表达，因此表明Slfn1可能通过下游靶点Cyclin D1调控EPCs的功能。以上实验结果可望为EPCs修复损伤血管内皮的机制认识展示一个新的视野，从而为冠心病、高血压等血管损伤性疾病的临床防治开拓新思路，提供新的潜在靶点。

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