TWEAK/Fn14通路在内皮祖细胞移植修复受损心肌中的作用及机制研究

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily and its receptor is Fn14. The level of TWEAK could be increased during ischemia and injury. The TWEAK could promote endothelial cell proliferation and angiogenesis. During acute myocardial infarction, the level of TWEAK/Fn14 in the myocardium was significantly up-regulated. TWEAK/Fn14 was involved in angiogenesis in ischemic myocardium. Moreover, TWEAK/Fn14 was also involved in regulating the proliferation and differentiation of various progenitor cells. Our preliminary experiment showed that TWEAK could improve the endothelial progenitor cell (EPCs) proliferation and migration, but the mechanism was unknown. In the present study, we will explore the effects and mechanisms of TWEAK/Fn14 on EPCs proliferation, migration and angiogenesis by using the technologies such as genetically modified, RNA interference and the blockers of signal pathway. In vivo, the mouse MI model is established and the EPCs are multimodal labeled. The labeled EPCs are traced by using near infrared fluorescence and 7.0 T MRI. In addition, the infarction size and Cardiac function are evaluated following EPCs transplantation. The TWEAK/Fn14 is verified to enhance the function of EPCs and thus improve cardiac performance. This study will provide new intervention strategies for EPCs transplantation in the treatment of acute myocardial infarction.

TWEAK是TNF超家族成员，受体是Fn14，缺血、损伤等应激时可上调，促进内皮细胞增殖及血管生成。急性心梗时TWEAK/Fn14 在心肌中皆明显上调，参与缺血心肌的血管生成。且此信号通路还参与调节多种祖细胞的增殖和分化。我们的预实验发现TWEAK 可提高内皮祖细胞(EPCs）增殖和迁移能力，但机制不明。本研究拟运用基因转染、RNA干扰、信号传导通路中多个调控单元的阻断等技术体外探讨TWEAK/Fn14在EPCs增殖、迁移及血管生成中的作用及其机制。通过小鼠MI模型，移植多模态探针标记EPCs，运用近红外荧光及超高磁场的7.0 T核磁共振技术动态、活体示踪标记的EPCs及评价EPCs移植后梗死区域血管新生与功能的改善。以验证TWEAK/Fn14促进EPCs的修复功能。为EPCs移植治疗急性心梗提供新的干预策略。

TWEAK是TNF超家族成员，受体是Fn14，缺血、损伤等应激时可上调，促进内皮细胞增殖及血管生成。急性心梗时TWEAK/Fn14 在心肌中皆明显上调，参与缺血心肌的血管生成。且此信号通路还参与调节多种祖细胞的增殖和分化。我们的预实验发现TWEAK 可提高内皮祖细胞(EPCs）增殖和迁移能力，但机制不明。本研究拟运用RNA干扰、信号传导通路中多个调控单元的阻断等技术体外探讨TWEAK/Fn14在EPCs增殖、迁移及血管生成中的作用及其机制。通过小鼠MI模型，移植近红外荧光标记EPCs，评价EPCs移植后梗死区域血管新生与功能的改善。以验证TWEAK/Fn14促进EPCs的修复功能。为EPCs移植治疗急性心梗提供新的干预策略。