SRF辅因子协同变化对房颤心房肌重构的调控作用研究

The molecular mechanisms of AF are poorly understood. Two major changes of atrial cell was supposed involve in the intrinsically progressive nature of AF. The first was electrical remodeling,and the second was structural remodeling .Together, these mechanisms contribute to the maintenance of AF. Several lines of evidence indicate that these atrial myocytes after sustained AF resemble immature muscle cells. The phenotypic resemblance with foetal cardiomyocytes point towards the nature of dedifferentiation of fibrillating atria which render the cardiomyocytes able to survive stress conditions. The transcriptional factor SRF has been shown to play an important role in regulating cell differentiation and proliferation. ELK-1 and smad1，members of transcription cofactors of SRF，was founded significantly expression changement in atrial tissue of patients with chronic AF compared to that with sinus rhythm in our earlier study. It's reasonable to presume that the transcription cofactors of SRF participated in the molecular and structural remodeling by which AF is sustained. In order to further ascertain the correlation between the transcriptional cofactors of SRF and the pathogenesis of chronic AF，we intend to observe the gene expression profile of the transcriptional cofactors of SRF in fibrillating atria by genechip,realtime RT-PCR and Western Blot，and investigate the genes function by gene overexpression and siRNA silence technology.

房颤心房肌出现电重构和结构重构，是房颤恶性发展的根本原因，但其发生、调控机制尚不清楚。既往研究证实SRF辅因子间存在相互联系，与血清反应因子SRF形成转录复合物，在细胞分化增生调节中起着关键作用，而反分化、增生及纤维化表现是房颤心房肌结构重构的典型特征。前期研究工作中我们先后观察到慢性房颤心房肌SRF辅因子ELK-1、smad1存在表达改变，因此推测：SRF辅因子协同变化在房颤心房肌重构中可能起着重要的调控作用。本课题拟利用表达谱基因芯片、实时RT-PCR、Western Blot等技术进一步明确房颤心房肌中SRF辅因子的表达变化状态，在此基础上构建心房肌特异性表达慢病毒载体，针对房颤心房细胞和羊房颤动物模型，施以SRF辅因子过表达、RNA沉默等基因干预，探讨SRF辅因子变化在房颤心房肌重构中的调控和协同作用，从而进一步揭示房颤的发病机制，为房颤的药物和基因治疗奠定基础。