Ca2+ signaling mechanisms in cardiac fibrosis

心脏纤维化中的 Ca2 信号传导机制

• 批准号: 8208016
• 负责人: Lixia Yue
• 金额: $ 38.21万
• 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/8208016
• 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、心脏僵硬的有害因素。 心室壁和收缩力丧失，从而导致多种心脏病，包括 肥大、心力衰竭和心律失常等多种刺激。 氧化应激可以诱导成纤维细胞分化并启动纤维发生级联反应。 心脏纤维形成机制的研究将为治疗方法提供新的见解 纤维化相关的心律失常、肥大和心力衰竭。 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+ 如何为心脏纤维形成以及纤维化相关的心脏病提供信号。 第一个资助期，我们在揭示心脏中的 Ca2+ 信号传导机制方面取得了实质性进展 首先，我们发现 TRPM7 是负责 Ca2+ 的关键 Ca2+ 渗透通道。 TRPM7 是主要 Ca2+- 分子机制的基础。 CF 中的渗透通道至关重要，因为它为我们探索潜在作用开辟了新途径 其次，我们发现 TRPM7 介导的 Ca2+ 是 TGF¿ 1 TGF-¿ 诱导成纤维细胞增殖、分化和胶原蛋白产生。 1 是主导 TRPM7 参与 TGF-¿ 1 信号通路表明 TRPM7 发挥作用 TRPM7 在心脏纤维形成中发挥重要作用，并且可以作为治疗靶点。 许多证据表明，介导的 Ca2+ 信号对纤维形成有显着贡献， 包括 TRPM7 在 AF 患者中显着上调，并且敲除 TRPM7 会损害 TGF-¿ 1 这些新发现使我们能够提出更多疑问。 广泛的问题：第一，Ca2+信号如何促进纤维形成？第二，TRPM7是否是一种信号？ 我们设计了三个具体目标来解决这些问题。 当前申请中的问题：1) 研究 Trpm7 的基因删除是否会减轻纤维化和 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 影响纤维发生？ 1 我们将应用多学科方法，包括分子生物学、生物化学、膜片钳、 Ca2+ 成像、转基因和基因敲除，以在分子、细胞、信号传导和免疫学方面探索这些问题 这项研究的结果不仅揭示了 Ca2+ 信号如何控制心脏。 纤维发生，还为纤维化心脏病的治疗方法提供临床见解。