GSK3β磷酸化修饰RNA结合蛋白FXR1改善HCM小鼠室性心律失常易感性的机制研究

批准号:
81900303
项目类别:
青年科学基金项目
资助金额:
21.0 万元
负责人:
黄亿源
依托单位:
学科分类:
H0204.心电活动异常与心律失常
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
--
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
心肌缝隙连接/Cx43重构是肥厚型心肌病(HCM)继发室性心律失常的病理基础,但其机制不清、缺乏防治靶点。本研究以RNA结合蛋白FXR1为新切入点,前期中意外发现其自身磷酸化修饰是HCM继发室性心律失常的潜在机制,基于①FXR1与CX43 mRNA直接结合调控其表达;②HCM小鼠心脏FXR1表达增加;③上调FXR1磷酸化水平降低其室性心律失常易感性;④FXR1磷酸化受GSK3β直接调控。据此提出假说:在HCM小鼠中,上调GSK3β磷酸化修饰FXR1,将抑制FXR1功能,改善心肌缝隙连接/Cx43重构,从而降低小鼠室性心律失常易感性。本研究拟采用基因突变型HCM小鼠和基因干预进行体内和体外实验,多手段探讨FXR1及其磷酸化调控在HCM继发室性心律失常中的作用和机制。本研究将从“RNA结合蛋白FXR1磷酸化修饰后失功能”这一新角度为防治HCM室性心律失常提供新思路和新靶点。
英文摘要
Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. RNA-binding proteins are triggered in response to hereditary cardiomyopathies. A latest study reveals that the expression level of Fragile X mental retardation autosomal homolog 1 (FXR1), an RNA-binding protein, is critical for gap junction remodeling; however, the connection between FXR1 and HCM is not clear. Recently, we found that the expression level of FXR1 was upregulated associated with downregulation of gap junction protein CX43 in a well-established HCM model, R92W TNT mice. Furthermore, treatment with a small molecule leads to the increasing of FXR1 phosphorylation, which prevents ventricular tachycardia showing functional significance of FXR1 upregulation observed in HCM. Recent studies show that FXR1 is a GSK3β substrate, and it is verified that GSK3β expression is decreased in HCM mice. To test our hypothesis that phosphorylation of FXR1 by GSK3β prevents gap junction downregulation, leading to the decrease of cardiac arrhythmogenesis in HCM, we sought to identify the mechanisms regulating gap junction remodeling in cardiac disease, how FXR1 regulates it targets through RNA stability and luciferase assays, and functional consequences of altering the levels of GSK3β and phosphorylation of FXR1 through the analysis of HCM mice with GSK3β upregulation or knockdown. This study might provide scientific and experimental direction for the treatment of ventricular tachycardia in HCM.
心肌肥厚是高血压、肺动脉高压、心脏瓣膜疾病等多种心血管疾病终末期心力衰竭的病理基础,然而,目前心肌肥厚的发病机制尚不明确,临床上对心肌肥厚及心力衰竭的治疗效果并不理想。因此,探索心肌肥厚的发病机制,寻找新的治疗靶点尤为重要。本项目前期发现HCM小鼠心肌中FXR1表达水平上调,磷酸化水平降低,小分子化合物Fropofol可促进FXR1蛋白磷酸化,结合Fropofol可以改善HCM小鼠心室重构及心脏功能,促使我们深入探讨FXR1对心肌肥厚的调控作用及可能的分子机制。本研究首先建立了TAC左心室肥厚模型及MCT诱导的PAH右心室肥厚模型,明确了FXR1在肥厚的心肌组织中表达增加;接着,采用蛋白获得实验证实了FXR1表达增加可以促进心肌细胞肥大;最后通过转录组测序及生物信息学分析阐明了FXR1可能通过调控线粒体的功能参与心肌肥厚的发生发展。
专著列表
科研奖励列表
会议论文列表
专利列表
国内基金
海外基金
