心肌细胞极化和心脏致密化不全的分子机制研究

项目名称： 心肌细胞极化和心脏致密化不全的分子机制研究

项目编号： No.81470446

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 寿伟年

作者单位： 中国医学科学院阜外医院

项目金额： 75万元

中文摘要： 心室壁发育中的室壁小梁和致密层的形态缺陷可以导致左室致密化不全（LVNC），进而导致心力衰竭。但LVNC的病因却缺乏深入的分子机制研究。在过去十年的工作中，我们确认了BMP10信号通路是调节心室壁发育的重要信号途径。我们最近的工作发现，非经典Wnt/PCP通路是建立心肌细胞极性、肌丝发生和调节致密层形成的调节因素，敲除Wnt / PCP信号通路中的Daam1基因可以导致心脏致密化不全。据此我们推测，心室小梁和致密层的形成可能由两个相互独立的信号途径参与：一种途径主要调节心肌细胞增殖，而另外一条途径则调节心肌细胞极化与肌丝发生。对此，我们的课题拟解决以下问题:1)确认Daam1是非经典Wnt信号通路中参与心室发育的调节因素 2)确认Pak1激酶是Daam1的负调控因子; 3)确认过度激活的Pak1蛋白和下调表达的Daam1蛋白导致心室致密化不全。该研究将有望阐明LVNC心肌病的分子发病机制。

中文关键词： 先天性心脏病；室壁致密化不全；Wnt；信号通路；细胞极化

英文摘要： Ventricular trabeculation and compaction are two interconnected morphogenetic events critical for ventricular wall formation. Altered genetic control of these events can lead to the Left Ventricular Noncompaction (LVNC), a recently classified inherited cardiomyopathy with marked thickening of trabeculae and increased intertrabecular recesses. The etiology and pathogenesis of LVNC are elusive largely due to the heterogeneity of the patients and the overall lack of understanding of the molecular mechanisms orchestrating ventricular trabeculation and compaction. In the past decade, by systematically analyzing the ventricular trabeculation and compaction in several genetically manipulated mice, we were able to identify several critical intercellular and intracellular signaling pathways contributing to normal ventricular wall development, which when disrupted give rise to ventricular hypertrabeculation and noncompaction. Recently, we have demonstrated that endocardial-endothelial Notch1 has an important role in regulating Neuregulin1 (NRG1)-ErbB2/4 signaling pathways and Bone Morphogenetic Protein 10 (BMP10)-mediated signaling pathway. The BMP10 pathway is critical to promote cardiomyocyte proliferation and regulate ventricular wall growth. Elevated level of BMP10 contributes to the ventricular hypertrabeculation. NRG1-ErbB2/4 signaling, however, is potentially a negative regulator of a non-canonical Wnt planner cell polarity (PCP), which is critical to establish cardiomyocyte polarity and myofibrillogenesis and regulate ventricular wall compaction. Enhanced NRG1-ErbB2/4 signaling likely contributes primarily to ventricular noncompaction. Recently, we have identified Dishevelled-associated activator of morphogenesis 1 (Daam1), an effector of Wnt/PCP signaling is down-regulated by NRG1 treatment. Genetic ablation of Daam1 leads to ventricular noncompaction. More importantly, the over-activation of one of the NRG1 down-stream signaling components p21-activated kinase 1 (Pak1) can negatively regulate Daam1 protein expression and function. We hypothesize that there are two independent, yet potentially interrelated, signaling pathways involved in the regulation of ventricular trabeculation and compaction: one primarily regulates cardiomyocyte proliferation and the other regulates cardiomyocyte polarization/myofibrillogenesis. This proposal builds upon these findings and will address the following questions: 1) if Daam1 is a down-stream effector of non-canonical Wnt signaling pathway in developing ventricular cardiomyocytes; 2) if the protein kinase Pak1 is a key negative regulator of Daam1; 3) if over-activation of Pak1 and down-regulation of Daam1 contributes to ventricular noncompaction. These studies will further validate and refine our novel working model for ventricular wall development, and will provide new insights into the molecular pathogenesis of ventricular noncompaction.

英文关键词： congenital heart disease;ventricular noncompaction;Wnt signaling pathway;cell polarity