Restrictive Cardiomyopathy Caused by Troponin Mutations: Application of Disease Animal Models in Translational Studies.
Restrictive Cardiomyopathy Caused by Troponin Mutations: Application of Disease Animal Models in Translational Studies.
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DOI：
10.3389/fphys.2016.00629
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发表时间：
2016
影响因子：
4
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Liu X;Zhang L;Pacciulli D;Zhao J;Nan C;Shen W;Quan J;Tian J;Huang X
心肌肌钙蛋白I(CTnI)在心功能调节中起重要作用。研究表明，cTnI缺乏或cTnI突变(特别是在cTnI的C末端)由于肌原纤维对钙的敏感性增加而导致舒张性功能障碍(松弛受损)。2003年，首次临床研究揭示了限制性心肌病(RCM)与心肌肌钙蛋白突变之间的关系。为了阐明cTnI突变导致心肌病的机制，我们建立了cTnI基因敲除小鼠模型和带有已报道的cTnI C末端点突变的转基因小鼠系。在本文中，我们总结了我们实验室使用这些动物模型进行的研究，以及使用重组纤维和培养细胞进行的其他体外研究。还讨论了这些cTnI C末端突变引起的舒张期功能障碍和心力衰竭的潜在机制。此外，还讨论了钙脱敏在纠正cTnI突变所致的心肌细胞松弛受损中的作用。最后，我们描述了一种从床边到板凳、从板凳到床边的翻译研究模式。这些研究可能会丰富我们对遗传性心肌病发病机制的理解，并为寻找针对舒张期功能障碍和心力衰竭的靶向药物提供线索。
Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. Studies have shown that the deficiency of cTnI or mutations in cTnI (particularly in the C-terminus of cTnI) results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium. The first clinical study revealing the association between restrictive cardiomyopathy (RCM) with cardiac troponin mutations was reported in 2003. In order to illustrate the mechanisms underlying the cTnI mutation caused cardiomyopathy, we have generated a cTnI gene knockout mouse model and transgenic mouse lines with the reported point mutations in cTnI C-terminus. In this paper, we summarize our studies using these animal models from our laboratory and the other in vitro studies using reconstituted filament and cultured cells. The potential mechanisms underlying diastolic dysfunction and heart failure caused by these cTnI C-terminal mutations are discussed as well. Furthermore, calcium desensitizing in correction of impaired relaxation in myocardial cells due to cTnI mutations is discussed. Finally, we describe a model of translational study, i.e., from bedside to bench and from bench to bedside. These studies may enrich our understanding of the mechanism underlying inherited cardiomyopathies and provide the clues to search for target-oriented medication aiming at the treatment of diastolic dysfunction and heart failure.
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影响因子：
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作者：
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发表时间：
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