以ERK信号通路为靶点治疗nesprin蛋白缺陷导致的扩张型心肌病的可行性研究

The diagnosis and treatment of dilated cardiomyopathy (DCM) is challenging because of its extremely complicated pathogenesis. Recent studies suggested nesprin defects were involved in the pathogenesis of DCM. However, the underlying mechanism remains unknown. To elucidate how nesprin mutations lead to DCM, we have generated cell models of nesprin defects. And our preliminary in vitro data showed nesprin mutations found in DCM patients caused disruption of nuclear envelop and aberrant activation of extracellular regulated protein kinases (ERK). Recent studies indicated an important role of ERK pathway in the pathogenesis of DCM. As a result, we hypothesis nesprin defects cause DCM through aberrant activation of the ERK pathway, which is potentially a novel target for drug therapy. In this project, we aim to generate an animal model of nesprin defects by cardiac specific transgene of nesprin KASH domain. Then, we will investigate the impact of nesprin defects on the ERK pathway in vivo in this animal model. Furthermore, we will try to prevent or rescue the phenotype caused by nesprin defects using ERK inhibitors. The results of this project may further our understanding of the pathogenic mechanism of DCM, and also shed light on new drug therapy for DCM.

扩张型心肌病（Dilated Cardiomyopathy，DCM）发病机制复杂，诊断和治疗困难。研究提示核膜蛋白nesprin的缺陷与DCM发病相关，但致病机制尚不清楚。课题组前期细胞实验表明DCM患者携带的nesprin突变可以导致细胞外调节蛋白激酶（extracellular regulated protein kinases，ERK）的异常激活。而最近的研究显示ERK信号通路的异常参与DCM发病。因此，我们提出假说认为ERK信号通路可能是nesprin缺陷导致DCM的重要致病机制和潜在的新药物靶点。本项目计划通过nesprin KASH片段心脏特异性转基因构建nesprin缺陷动物模型。在此动物模型中验证nesprin缺陷对ERK信号通路的影响，并观察ERK抑制剂能否预防和治疗nesprin缺陷导致的表型。本研究将有助于深入阐明DCM发病机制，并为DCM的新靶向药物的研发奠定基础。

基于前期体外实验结果，课题组提出假说：细胞外调节蛋白激酶（extracellular regulated protein kinases，ERK）信号通路的异常激活可能是nesprin缺陷导致（Dilated Cardiomyopathy，DCM）的重要致病机制。本项目通过nesprin KASH片段心脏特异性转基因构建nesprin缺陷动物模型。但该KASH心脏特异性转基因小鼠并未出现DCM表型，反而出现心肌肥厚表型。为了验证ERK信号通路在DCM发病中的作用，课题组通过阿霉素诱导建立大鼠DCM模型，在此动物模型中发现ERK信号通路的激活，而一种新型抗肿瘤药selumetinib可对心肌细胞ERK信号通路的异常激活起到抑制作用，从而挽救动物模型的DCM表型。上述结果初步表明ERK信号通路的异常激活可能是DCM的重要共同致病机制，ERK信号通路抑制剂可能是DCM新的治疗靶点。此外，课题组还发现selumetinib可能通过抑制ERK信号通路起到预防心肌肥厚的作用，为心肌肥厚的治疗提供了新的思路。