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: 8692593
• 负责人: Janelle Rowell
• 金额: $ 3.71万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692593
• 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; public health relevance; 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.

描述（由申请人提供）：典型瞬时受体电位（TRPC）通道与钙调神经磷酸酶-活化T细胞核因子（Cn- NFAT）信号传导介导的适应不良性心脏肥大相关。然而，对通道活动的调节还没有很好地理解。我们的实验室已经报道了PKG磷酸化抑制TRPC 6活性的一种调节机制。在HEK 293细胞中的研究表明TRPC通道活性也可以通过门控基质相互作用蛋白-1（Stim 1）来调节，该蛋白最近被报道有助于体内的肥大反应。初步数据表明，Stim 1和TRPC 6通道耦合可能会影响PKG抑制通道。这项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。通过更好地了解TRPC通道的调节，这在心脏病理学的实验和模型中很重要，并且在人类心脏病中也被上调，我们将了解有关治疗靶点的线索。我们假设STIM 1与心肌细胞中的TRPC 3和TRPC 6通道相互作用，导致NFAT介导的钙离子进入和肥大信号增加。此外，我们认为心肌细胞中Stim 1和TRPC 3/6通道的偶联阻止了PKG磷酸化。我们将通过检查离体心肌细胞中的钙内流来测试这一点，并在体内探索心脏肥大的啮齿动物模型中Stim 1和TRPC通道之间的相互作用。