Role of serum- and glucocorticoid-regulated kinase-1 in electrical remodeling

血清和糖皮质激素调节激酶 1 在电重构中的作用

基本信息

批准号：
8206688
负责人：
ANTHONY ROSENZWEIG
金额：
$ 43.07万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206688
关键词：
1-Phosphatidylinositol 3-Kinase Action Potentials Address Arrhythmia Binding Cardiac Cardiac Myocytes Characteristics Chronic Data Development Dominant-Negative Mutation Electrophysiology (science)Exhibits Fibrosis Functional disorder Genetic Genomics Goals Growth Heart Heart Hypertrophy Heart failure Hypertrophy In Vitro Investigation Ion Channel Kinetics Maps Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Mus Mutagenesis Myocardium Optics Pathway interactions Patients Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Physiological Play Post-Translational Protein Processing Potassium Channel Protein-Serine-Threonine Kinases Proteins Proteomics Relative (related person)Risk Role Sgk protein Signal Transduction Sodium Sodium Channel System Testing Tissues Transgenic Mice base constriction drug development heart rhythm in vivo inhibitor/antagonist interest mortality novel novel therapeutic intervention public health relevance therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Adverse cardiac remodeling is a common prelude to heart failure and arrhythmia, but little is known about the signaling mechanisms that mediate this transition. Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a PI3-kinase (PI3K)-dependent kinase that is activated in pathological hypertrophy and heart failure (HF) but not in physiological hypertrophy. SGK1 shares some downstream substrates (e.g. GSK3 and Foxo3) with other PI3K-dependent kinases, such as Akt1, but also has unique downstream effects including modulation of ion channels such as potassium channels and the cardiac sodium channel, SCN5a. While we have previously shown that SGK1 regulates cardiomyocyte (CM) survival and growth in vitro, its role in CM in vivo and the effects of chronic SGK1 activation or inhibition are largely unknown. To address these questions in vivo, we generated cardiac-specific transgenic (TG) mice expressing either a constitutively active (CA) or dominant negative (DN) form of the SGK1 kinase. While SGK1-CA TG mice exhibit spontaneous and inducible arrhythmias, SGK1-DN TG mice appear normal at baseline. In a model of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC), SGK1-DN TGs are substantially protected against cardiac dysfunction and fibrosis. SGK1 activation led to significant alterations in post-translational modification and subcellular distribution of SCN5a protein. This was associated with altered channel kinetics and gating, as well as an increase in late sodium current (INaL) and action potential duration (APD). The major goal of this proposal is to understand the role of SGK1 in electrical remodeling in the context of pathological hypertrophy and HF. This proposal is based on four hypotheses: 1) that chronic activation of SGK1 in CMs is an important mediator of adverse electrical remodeling in HF, 2) that inhibition of SGK1 in CMs will mitigate adverse remodeling, 3) that altered SCN5a function and INaL are important contributors to these effects, and 4) that other novel SGK1 substrates also play a role in the observed phenotypes. To test these hypotheses, we will utilize mice with CM-specific expression of SGK1-CA or -DN at baseline and in models of hypertrophy and/or HF. In Aim 1, we will examine the effects of activating or inhibiting SGK1 on electrical remodeling at baseline and after aortic banding. In Aim 2, we will define the cellular mechanisms responsible for the observed electrophysiological phenotypes. Finally, in Aim 3, we will delineate the molecular mechanisms mediating these phenotypes through focused interrogation of known downstream pathways, and subtractive screens for novel effectors. Arrhythmia remains an important cause of morbidity and mortality in HF. Understanding the role of SGK1 in adverse electrical remodeling and arrhythmic complications of HF could yield novel therapeutic approaches for this important condition. PUBLIC HEALTH RELEVANCE: Patients with heart failure or thickened (hypertrophied) heart muscle are at increased risk for heart rhythm problems, some of which can be fatal. Our goal is to understand the role of a specific molecule (SGK1) in the development of heart rhythm problems in this context. We will study this question in mice in which we have genetically activated or inhibited this molecule specifically in heart muscle cells. Our initial results suggest that activating this molecule promotes rhythm problems, whereas inhibiting it has beneficial effects. While we think it is important in general to understand mechanisms underlying heart rhythm problems, this molecule is particularly interesting because it belongs to a class of molecules that have previously been successfully targeted for drug development. Thus understanding SGK1's role in the heart could have important practical implications, and the current application would help advance our understanding of the potential of SGK1 as a therapeutic target.

描述（由申请人提供）：不良心脏重塑是心力衰竭和心律失常的常见前奏，但人们对介导这种转变的信号传导机制知之甚少。血清和糖皮质激素调节激酶 1 (SGK1) 是一种 PI3 激酶 (PI3K) 依赖性激酶，在病理性肥大和心力衰竭 (HF) 中激活，但在生理性肥大中不激活。 SGK1 与其他 PI3K 依赖性激酶（例如 Akt1）共享一些下游底物（例如 GSK3 和 Foxo3），但也具有独特的下游效应，包括调节钾通道和心脏钠通道 SCN5a 等离子通道。虽然我们之前已经证明 SGK1 在体外调节心肌细胞 (CM) 存活和生长，但其在体内 CM 中的作用以及慢性 SGK1 激活或抑制的影响在很大程度上尚不清楚。为了在体内解决这些问题，我们培育了表达 SGK1 激酶的组成型活性 (CA) 或显性失活 (DN) 形式的心脏特异性转基因 (TG) 小鼠。 SGK1-CA TG 小鼠表现出自发性和诱导性心律失常，而 SGK1-DN TG 小鼠在基线时表现正常。在横主动脉缩窄 (TAC) 诱导的心脏肥大和心力衰竭模型中，SGK1-DN TG 可以显着防止心脏功能障碍和纤维化。 SGK1 激活导致 SCN5a 蛋白的翻译后修饰和亚细胞分布发生显着变化。这与通道动力学和门控的改变以及晚钠电流 (INaL) 和动作电位持续时间 (APD) 的增加有关。该提案的主要目标是了解 SGK1 在病理性肥大和心力衰竭背景下电重塑中的作用。该提议基于四个假设：1) CM 中 SGK1 的慢性激活是 HF 中不良电重塑的重要介质，2) CM 中 SGK1 的抑制将减轻不良重塑，3) SCN5a 功能和 INaL 的改变是这些效应的重要贡献者，4) 其他新型 SGK1 底物也在观察到的表型中发挥作用。为了测试这些假设，我们将利用在基线和肥大和/或心力衰竭模型中具有 CM 特异性表达 SGK1-CA 或 -DN 的小鼠。在目标 1 中，我们将检查激活或抑制 SGK1 对基线和主动脉结扎后电重塑的影响。在目标 2 中，我们将定义导致观察到的电生理表型的细胞机制。最后，在目标 3 中，我们将通过对已知下游途径的集中询问和新效应子的消减筛选来描述介导这些表型的分子机制。心律失常仍然是心力衰竭发病和死亡的重要原因。了解 SGK1 在心力衰竭不良电重塑和心律失常并发症中的作用可能会为这种重要疾病产生新的治疗方法。公共卫生相关性：患有心力衰竭或心肌增厚（肥大）的患者出现心律问题的风险增加，其中一些可能是致命的。我们的目标是了解特定分子 (SGK1) 在这种情况下心律问题发展中的作用。我们将在小鼠中研究这个问题，在这些小鼠中，我们通过基因激活或抑制了这种分子，特别是在心肌细胞中。我们的初步结果表明，激活该分子会导致节律问题，而抑制它则具有有益的作用。虽然我们认为了解心律问题背后的机制总体上很重要，但这种分子特别有趣，因为它属于先前已成功用于药物开发的一类分子。因此，了解 SGK1 在心脏中的作用可能具有重要的实际意义，当前的应用将有助于加深我们对 SGK1 作为治疗靶点潜力的理解。