Ca2+ signaling mechanisms in cardiac fibrosis

心脏纤维化中的 Ca2 信号传导机制

• 批准号: 8043415
• 负责人: Lixia Yue
• 金额: $ 38.07万
• 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/8043415
• 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

DESCRIPTION (provided by applicant): 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 TGF21 induced fibroblast proliferation, differentiation, and collagen production. Since TGF-21 is the predominant mediator for fibrogenesis, the involvement of TRPM7 in TGF-21 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-21 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 TGF21 production. We will apply multidisciplinary approaches including molecular biology, biochemistry, patch-clamp, Ca2+ imaging, transgenic and knockout to explore these questions 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. PUBLIC HEALTH RELEVANCE: Cardiac fibrosis is a detrimental factor which causes a variety of heart diseases including hypertrophy, heart failure and arrhythmia. Here we propose to investigate Ca2+ signaling mechanisms in mouse and human fibroblasts and to study how the Ca2+ permeable channel TRPM7 contribute to fibrosis related heart diseases. The results of this project will not only provide novel information about fundamental question regarding how Ca2+ signaling is involved in fibrogenesis, but also may provide a novel therapeutic target for fibrosis related heart diseases.

描述（申请人提供）：心脏纤维化是一种有害因素，导致心脏传导异常、心室壁僵硬和收缩力丧失，从而导致多种心脏疾病，包括肥厚、心力衰竭和心律失常。梗塞、压力超负荷和氧化应激等多种刺激可以诱导成纤维细胞分化并启动纤维发生级联反应。更好地了解心脏纤维形成的机制将为治疗纤维化相关心律失常、肥厚和心力衰竭的治疗方法提供新的见解。 该研究项目的目标是了解心脏成纤维细胞 (CF) 中的 Ca2+ 信号传导机制以及 Ca2+ 信号如何促进心脏纤维形成以及纤维化相关的心脏病。在第一个资助期间，我们在揭示心脏纤维形成中的Ca2+信号传导机制方面取得了实质性进展。首先，我们发现TRPM7是关键的Ca2+通透通道，负责Ca2+进入心脏成纤维细胞。 TRPM7 是 CF 中主要 Ca2+- 通透通道分子机制的基础这一发现具有重要意义，因为它为我们探索 Ca2+ 信号在心脏纤维形成中的潜在作用开辟了一条新途径。其次，我们发现TRPM7介导的Ca2+是TGF21诱导成纤维细胞增殖、分化和胶原蛋白产生所必需的。由于TGF-21是纤维发生的主要介质，TRPM7参与TGF-21信号通路表明TRPM7在心脏纤维发生中发挥重要作用，并且可以作为治疗靶点。事实上，我们发现 TRPM7 介导的 Ca2+ 信号对纤维形成有显着贡献，正如许多证据所证明的那样，包括 TRPM7 在 AF 患者中显着上调，敲除 TRPM7 会损害 TGF-21 介导的成纤维细胞分化和胶原蛋白产生。这些新发现使我们能够提出更深刻的问题：首先，Ca2+信号如何促进纤维形成？其次，TRPM7是否是纤维化相关心脏病的潜在靶点。我们设计了三个具体目标来解决当前应用中的这些问题：1）研究TRPM7的基因删除是否可以减轻纤维化并改善心脏功能； 2）确定TRPM7介导的Ca2+信号参与心脏纤维形成的信号通路； 3) 研究TRPM7是否通过增强TGF21的产生来影响纤维发生。我们将应用分子生物学、生物化学、膜片钳、Ca2+成像、转基因和基因敲除等多学科方法在分子、细胞、信号传导和体内动物模型水平上探索这些问题。这项研究的结果不仅将揭示 Ca2+ 信号如何控制心脏纤维形成，还将为纤维化心脏病的治疗方法提供临床见解。 公众健康相关性：心脏纤维化是一种有害因素，可导致多种心脏病，包括肥厚、心力衰竭和心律失常。在这里，我们建议研究小鼠和人类成纤维细胞中的 Ca2+ 信号传导机制，并研究 Ca2+ 通透通道 TRPM7 如何促进纤维化相关的心脏病。该项目的结果不仅将为有关Ca2+信号如何参与纤维发生的基本问题提供新的信息，而且还可能为纤维化相关的心脏病提供新的治疗靶点。