Influence of Stim1 on TRPC post-translational modulation and cardiac hypertrophy

Stim1 对 TRPC 翻译后调节和心脏肥大的影响

• 批准号: 8400718
• 负责人: Janelle Rowell
• 金额: $ 4.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8400718
• 关键词: Address; Affect; Calcineurin; Calcium; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Chronic; Coupled; Coupling; Cyclic GMP-Dependent Protein Kinases; Data; Development; Employee Strikes; Experimental Models; G-Protein-Coupled Receptors; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; Individual; Learning; Link; Mediating; Modeling; Molecular; Monitor; Mus; Muscle Cells; Pathologic; Pathology; Pathway interactions; Phosphorylation; Play; Population; Post-Translational Protein Processing; Process; Protein Dephosphorylation; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Rodent Model; Role; Signal Transduction; Site; Stress; Stretching; Surface; Testing; Ventricular Remodeling; Work; calcineurin phosphatase; constriction; human STIM1 protein; in vivo; insight; loss of function; mutant; nuclear factors of activated T-cells; pressure; prevent; receptor; response; transcription factor

DESCRIPTION (provided by applicant): Canonical transient receptor potential (TRPC) channels are linked in maladaptive cardiac hypertrophy mediated by calcineurin-nuclear factor of activated T cells (Cn- NFAT) signaling. Yet, the regulation of channel activity is not well understood. Our lab has reported on one regulatory mechanism of by which PKG phosphorylation inhibits TRPC6 activity. Studies in HEK293 cells indicate TRPC channel activity may also be modulated by gating of stromal interacting protein-1 (Stim1) which was recently reported to contribute to the hypertrophic response in vivo. Preliminary data suggests that Stim1 and TRPC6 channel coupling may influence PKG inhibition of the channel. The proposed work has the potential to advance our understanding of the molecular mechanisms of cardiac hypertrophy and subsequent heart failure. By better understanding the modulation of TRPC channels, which are important in experimental and models of cardiac pathology and are also upregulated in human heart disease, we will learn clues about targets for therapy. We hypothesize that STIM1 interacts with TRPC3 and TRPC6 channels in the cardiomyocyte leading to increased calcium entry and hypertrophic signaling mediated by NFAT. Additionally, we propose that the coupling of Stim1 and TRPC3/6 channels in the cardiomyocyte prevents PKG phosphorylation. We will test this by examining the calcium influx in isolated cardiomyocytes, and in vivo we will explore the interaction between Stim1 and TRPC channels in rodent models of cardiac hypertrophy. PUBLIC HEALTH RELEVANCE: Canonical transient potential receptor (TRPC) channels play a role in the development of heart failure. It is not understood how the channel activity is regulated in the setting of cardiac pathology but stromal interaction molecule 1 (Stim1) may play an important role. We seek to explore this relationship and gain insight to development of heart failure in an effort to identify ways to inhibit the process.

描述（由申请人提供）：典型瞬时受体电位（TRPC）通道与激活T细胞的钙调磷酸酶-核因子（Cn-NFAT）信号转导介导的适应不良心脏肥大相关。然而，对渠道活动的监管尚不清楚。我们实验室报道了一种PKG磷酸化抑制TRPC6活性的调节机制。 HEK293 细胞研究表明，TRPC 通道活性也可能通过基质相互作用蛋白 1 (Stim1) 的门控来调节，最近报道称基质相互作用蛋白 1 有助于体内肥大反应。初步数据表明 Stim1 和 TRPC6 通道耦合可能影响 PKG 对通道的抑制。拟议的工作有可能促进我们对心脏肥大和随后的心力衰竭的分子机制的理解。 TRPC 通道在心脏病学实验和模型中非常重要，并且在人类心脏病中也会上调，通过更好地了解 TRPC 通道的调节，我们将了解有关治疗靶点的线索。我们假设 STIM1 与心肌细胞中的 TRPC3 和 TRPC6 通道相互作用，导致钙进入增加和 NFAT 介导的肥大信号传导。此外，我们提出心肌细胞中 Stim1 和 TRPC3/6 通道的偶联可防止 PKG 磷酸化。我们将通过检查离体心肌细胞中的钙流入来测试这一点，并且在体内我们将探索啮齿动物心脏肥大模型中 Stim1 和 TRPC 通道之间的相互作用。 公共健康相关性：规范瞬态电位受体 (TRPC) 通道在心力衰竭的发展中发挥作用。目前尚不清楚在心脏病理学背景下通道活性如何受到调节，但基质相互作用分子 1 (Stim1) 可能发挥重要作用。我们试图探索这种关系并深入了解心力衰竭的发展，以找出抑制这一过程的方法。