miR-21在TGF-β-Smad3信号介导的马凡氏综合症动脉瘤中的作用及机制研究

Exploring effectve therapeutic targets to Inhibit the dilation and rupture of Marfan aneurysm is key issues and challenges.Inhibition the activation of Nocanonical TGF-βsignaling ERK(extracellular regulated protein kinases) and JNK(c-Jun N-terminal kinases) could inhibit the dilation and rupture of Marfan aneurysm. miR-21 (small RNA-21, microRNA-21) could downregulate the expression of target gene Spry1 (sprouty homolog 1) and Pdcd4 (programmed cell death protein 4) to promote the activation of ERK and JNK.Our group and other laboratory studies showed that miR-21 was elevated in the aneurysm tissues, miR-21 antagonist could inhibited the dilation and rupture of aneurysm in Smad3+/- mice infused Ang-II(Angiotensin II) by inhibit the activation of ERK/JNK,which is a subject worthy of study. But the role of miR-21 in marfan aneurysm and it's upstream regulatory mechanisms is unclear.This study will chose the Marfan mice as research subjects to antagonize or knockout the miR-21 gene expression to explore the role of miR-21 in Marfan syndrome aneurysms by employing cytology, molecular biology, pathology technology. And from the TGF-β-Smad3 pathway to explore the regulatory mechanism miR-21 expression.This project will provide new experimental evidence for improving treatment strategies to Marfan syndrome aneurysm.....

寻找有效的靶点，早期控制马凡氏综合征动脉瘤的扩张及破裂，是目前国际上研究的重点和难点。拮抗TGF-β非经典通路分子ERK和JNK的活化，可以有效抑制动脉瘤的扩张和破裂。miR-21可以通过下调靶基因Spry1和Pdcd4的表达而促进ERK和JNK的活化。本课题组与其他实验室的研究均表明，动脉瘤组织中miR-21的表达异常升高，拮抗miR-21可以抑制Ang-II诱导的Smad3+/-小鼠主动脉根部ERK和JNK的活化及动脉的扩张，显示其在胸主动脉瘤扩张方面有重要的研究价值。但是其在马凡综合症动脉瘤中的作用及机制尚不明确。本研究将通过拮抗或者敲除miR-21，采用细胞学、分子生物学、病理学等技术来明确其在马凡氏综合征动脉瘤中的确切作用，并从TGF-β-Smad3途径来探讨调控miR-21表达的机制。为完善马凡氏综合征动脉瘤的的治疗策略提供了新的实验依据。