Ca2+ signaling mechanisms in cardiac fibrosis

心脏纤维化中的 Ca2 信号传导机制

• 批准号: 8392243
• 负责人: Lixia Yue
• 金额: $ 36.37万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392243
• 关键词: Address; Adverse effects; Angiotensin II; Animal Model; Arrhythmia; Attenuated; Biochemistry; Calcineurin; Cardiac; Clinical; Collagen; Data; Development; Extracellular Matrix; Fibroblasts; Fibrosis; Funding; Goals; Heart Diseases; Heart failure; Human; Hypertrophy; Image; Infarction; Interleukin-6; Knock-out; Knockout Mice; Mediating; Mediator of activation protein; Molecular; Molecular Biology; Mus; Myocardial Infarction; Myofibroblast; Oxidative Stress; Pathologic; Patients; Play; Production; Research; Role; Signal Pathway; Signal Transduction; Stimulus; Therapeutic; Transgenic Organisms; Ventricular; calmodulin-dependent protein kinase II; cytokine; design; fibrogenesis; heart function; improved; in vivo; insight; interdisciplinary approach; knock-down; new therapeutic target; novel; patch clamp; pressure; programs; research study; therapeutic target

SUMMARY Cardiac fibrosis is a detrimental factor that results in abnormalities in cardiac conduction, stiffening of the ventricular walls, and loss of contractility, thereby contributing to a variety of heart diseases, including hypertrophy, heart failure, and arrhythmia. A variety of stimuli such as infarction, pressure-overload, and oxidative stress can induce fibroblast differentiation and initiate fibrogenesis cascade. A better understanding of the mechanisms of cardiac fibrogenesis will provide novel insight into therapeutic approaches for treatment of fibrosis associated arrhythmia, hypertrophy and heart failure. The goal of this research program is to understand Ca2+ signaling mechanisms in cardiac fibroblasts (CFs) and how Ca2+ signals contribute to cardiac fibrogenesis as well as fibrosis associated heart diseases. In the first funding period, we have made substantial progress in revealing Ca2+ signaling mechanisms in cardiac fibrogenesis. First, we found that TRPM7 is the key Ca2+-permeable channel which is responsible for Ca2+ entry in cardiac fibroblasts. The finding that TRPM7 underlies the molecular mechanism of the major Ca2+- permeable channel in CFs is fundamental because it opens a new avenue for us to explore the potential roles of Ca2+ signals in cardiac fibrogenesis. Second, we found that TRPM7-mediated Ca2+ is required for TGF¿1 induced fibroblast proliferation, differentiation, and collagen production. Since TGF-¿1 is the predominant mediator for fibrogenesis, the involvement of TRPM7 in TGF-¿1 signaling pathway suggests that TRPM7 plays an essential role in cardiac fibrogenesis, and may serve as a therapeutic target. Indeed, we found that TRPM7 mediated Ca2+ signal contributes significantly to fibrogenesis as demonstrated by many lines of evidence, including that TRPM7 is markedly up-regulated in AF patients and that knocking down TRPM7 impairs TGF-¿1 mediated fibroblasts differentiation and collagen production. These novel findings allow us to ask more profound questions: First, how does Ca2+ signal contribute to fibrogenesis? Second, whether TRPM7 is a potential target for fibrosis related heart diseases. We have designed three specific aims to address these questions in the current application: 1) Investigate if genetically deletion of Trpm7 attenuates fibrosis and improves heart function; 2) Determine the signaling pathways by which TRPM7-mediated Ca2+ signals are involved in cardiac fibrogenesis; 3) Investigate whether TRPM7 influences fibrogenesis by enhancing TGF¿1 production. We will apply multidisciplinary approaches including molecular biology, biochemistry, patch-clamp, Ca2+ imaging, transgenic and knockout to explore these question at the molecular, cellular, signaling, and in vivo animal model levels. The results of this study will not only reveal how Ca2+ signaling controls cardiac fibrogenesis, but also provide clinical insight into therapeutic approaches for fibrotic heart diseases.

概括 心脏纤维化是导致心脏传导异常的有害因素 心室壁和收缩性丧失，从而导致各种心脏病，包括 肥大，心力衰竭和心律不齐。各种刺激，例如梗塞，压力越过和 氧化应激会诱导成纤维细胞分化并启动纤维发生级联反应。更好的理解 心脏纤维化的机制将提供对治疗方法的新见解 纤维化相关的心律失常，肥大和心力衰竭。 该研究计划的目的是了解心脏成纤维细胞中的CA2+信号传导机制（CFS） 以及CA2+信号如何促进心脏纤维发生以及纤维化相关的心脏病。在 首先，我们在揭示心脏的CA2+信号传导机制方面取得了重大进展 纤维发生。首先，我们发现TRPM7是负责CA2+的关键CA2+可渗透通道 进入心脏成纤维细胞。 TRPM7的发现是主要Ca2+ - 的分子机理的基础 CFS中的可渗透渠道是基本的，因为它为我们探索潜在角色开辟了新的途径 心脏纤维发生中的Ca2+信号。其次，我们发现TGF®需要TRPM7介导的Ca2+ 诱导的成纤维细胞增殖，分化和胶原蛋白产生。由于TGF-€1是主要的 纤维化介质，TRPM7参与TGF-€1信号通路表明TRPM7播放 心脏纤维发生中的重要作用，可以用作治疗靶点。确实，我们发现TRPM7 介导的Ca2+信号对纤维发生有显着贡献，如许多证据线证明， 包括该AF患者的TRPM7明显上调，而击倒TRPM7会损害TGF-€1 介导的成纤维细胞分化和胶原蛋白产生。这些新颖的发现使我们能够问更多 深刻的问题：首先，Ca2+信号如何促进纤维发生？第二，是否TRPM7是一个 纤维化相关心脏病的潜在靶标。我们设计了三个特定的目标来解决这些 当前应用中的问题：1）调查trpm7的一般缺失是否会减弱纤维化和 改善心脏功能； 2）确定TRPM7介导的Ca2+信号的信号通路 参与心脏纤维发生； 3）研究TRPM7是否通过增强TGF€1来影响纤维发生 生产。我们将采用多学科方法，包括分子生物学，生物化学，斑块钳， Ca2+成像，转基因和敲除，以探索分子，细胞，信号和中的这些问题 体内动物模型水平。这项研究的结果不仅会揭示CA2+信号传导如何控制心脏 纤维发生，但也为纤维化心脏病的治疗方法提供了临床见解。