Non-junctional roles of desmosome proteins in the pathogenesis of arrhythmogenic cardiomyopathy

桥粒蛋白在致心律失常性心肌病发病机制中的非连接作用

基本信息

项目摘要

PROJECT SUMMARY Cardiovascular diseases remain the major cause of death in the US. Recent advances in reprogramming somatic cells from cardiac patients into induced pluripotent stem cells (iPSCs) enables in vitro modeling of human cardiac diseases for pathogenic studies and therapeutic screens. Traditionally, weakened desmosome junctions are considered the main pathogenic mechanism for Arrhythmogenic Cardiomyopathy (AC), caused by mutations in five desmosome component proteins. Pathological hallmarks of AC are progressive fibro-fatty replacement of cardiomyocytes (CMs) with increased CM apoptosis primarily in the RV, leading to sudden death in the young. We have established a novel method to induce adult-like, fatty acid oxidation-dominant metabolism of primitive CMs derived from iPSCs (iPSC-CMs) and established the first metabolic maturation- based in vitro cardiac disease model for elucidation of novel pathogenic insights for human AC (Nature, 2013). We showed that abnormal PPARγ activation after normal PPARα-mediated metabolic maturation in AC CMs resulted in exaggerated lipogenesis, apoptosis, sodium channel deficits and defective Ca2+ handling in CMs with desmosome mutations, recapitulating the pathological signatures of AC hearts. Using our AC model and samples from pathological human AC hearts, we show here that plakoglobin is a key component of Insulin-p85 metabolic signaling complex. Desmosome mutations lead to faster plakoglobin degradation, reduce PI3K/Akt activation, and hyperactivate GSK3β, which downregulate a microRNA (miR) cluster leading to subsequent abnormal PPARγ activation and CM apoptosis. Importantly, we used genetic and cellular methods to confirm the clinically relevance of our pathogenic pathways in human AC hearts and in mouse models of AC. We propose here to further elucidate the dysregulated and non-junctional signaling networks caused by plakoglobin deficits, to study how plakophilin-2 deficits deregulate additional signaling pathways, and to find clinically safe therapeutic agents for treating AC using both in vitro iPSC-CM based models and mouse models of AC.
项目摘要 心血管疾病仍然是美国的主要死亡原因。重编程的最新进展 将来自心脏病患者的体细胞转化为诱导的多能干细胞(iPSC)能够在体外建模, 用于人类心脏疾病的病原学研究和治疗筛选。传统上,弱化的桥粒 连接被认为是致心律失常性心肌病(AC)的主要致病机制, 通过五种桥粒组成蛋白的突变。AC的病理特征是进行性纤维脂肪变性 心肌细胞(CM)的替代与增加CM凋亡主要在RV,导致突然 年轻人的死亡。我们已经建立了一种新的方法来诱导成人样,脂肪酸氧化为主的 - 来自iPSC的原始CM(iPSC-CM)的代谢,并建立了第一个代谢成熟- 基于体外心脏病模型,用于阐明人类AC的新致病见解(Nature,2013)。 我们发现,在ACCM中,正常的PPARα介导的代谢成熟后, 导致CM中过度的脂肪生成、细胞凋亡、钠通道缺陷和Ca 2+处理缺陷 桥粒突变,重现了AC心脏的病理特征。使用我们的AC模型, 从病理人类AC心脏的样本,我们在这里表明,斑珠蛋白是胰岛素-p85的关键组成部分 代谢信号复合物桥粒突变导致斑珠蛋白降解加快,PI 3 K/Akt降低 激活,并过度激活GSK 3 β,其下调microRNA(miR)簇,导致随后的 异常的PPARγ激活和CM凋亡。重要的是,我们使用遗传和细胞方法来证实 我们的致病途径在人类AC心脏和AC小鼠模型中的临床相关性。我们 在此,我建议进一步阐明由以下原因引起的失调和非连接信号网络: 斑珠蛋白缺陷,研究斑嗜蛋白-2缺陷如何解除额外的信号通路,并发现 使用基于iPSC-CM的体外模型和小鼠模型治疗AC的临床安全的治疗剂 的AC。

项目成果

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HUEI-SHENG Vincent CHEN其他文献

HUEI-SHENG Vincent CHEN的其他文献

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{{ truncateString('HUEI-SHENG Vincent CHEN', 18)}}的其他基金

Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
  • 批准号:
    7952509
  • 财政年份:
    2010
  • 资助金额:
    $ 50.16万
  • 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
  • 批准号:
    8118810
  • 财政年份:
    2010
  • 资助金额:
    $ 50.16万
  • 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
  • 批准号:
    8686923
  • 财政年份:
    2010
  • 资助金额:
    $ 50.16万
  • 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
  • 批准号:
    8489332
  • 财政年份:
    2010
  • 资助金额:
    $ 50.16万
  • 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
  • 批准号:
    8281434
  • 财政年份:
    2010
  • 资助金额:
    $ 50.16万
  • 项目类别:

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