PI3K signaling and channelopathies in the heart

心脏中的 PI3K 信号传导和通道病

• 批准号: 9295021
• 负责人: RICHARD Z LIN
• 金额: $ 43.82万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295021
• 关键词: Action Potentials; Adenoviruses; Animals; Antibodies; Arrhythmia; Autonomic nervous system; Biochemical; Biophysics; Bradyarrhythmias; Cardiac; Cardiac Surgery procedures; Cardiac conduction system; Cations; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complication; Complications of Diabetes Mellitus; Cyclic AMP; Cyclic Nucleotides; Data; Dependence; Development; Diabetes Mellitus; Down-Regulation; Electrocardiogram; Electrophysiology (science); Exhibits; Family; HCN4 gene; Healthcare; Heart; Heart Abnormalities; Heart Atrium; Heart Diseases; Heart Rate; High Fat Diet; Human; Incidence; Insulin; Insulin Resistance; Ion Channel; Ions; Left; Long QT Syndrome; Mass Spectrum Analysis; Measures; Mediating; Membrane; Molecular; Mus; Muscle Cells; Mutagenesis; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pacemakers; Patient Schedules; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiology; Population; Prevalence; Property; Protein Isoforms; Reporting; Risk; Signal Transduction; Sinoatrial Node; Site; Sodium; Sodium Channel; Sodium Channel Blockers; Structure of purkinje fibers; Sudden Death; Testing; Therapeutic; Tissue Harvesting; Tissue Sample; Tissues; Ventricular; autonomic nerve; base; cardiovascular risk factor; cohort; cyclic-nucleotide gated ion channels; design; diabetes management; diabetic; diabetic patient; digital; electrical property; experimental study; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; nodal myocyte; non-diabetic; phosphoproteomics; prevent; response; small hairpin RNA; sudden cardiac death; trafficking; voltage

With the rapid rise in the incidence and prevalence of obesity and type 2 diabetes, diabetic complications pose a heavy healthcare burden in the U.S.A. and throughout the world. This proposal is based on the innovative idea that insulin/PI3K signaling regulates ion currents in the heart, and channelopathies caused by reduced PI3K signaling contribute to the development of diabetic arrhythmogenic complications. The proposal investigates how PI3K signaling regulates the function of (1) a nonselective cation channel (HCN) that modulates the firing of pacemakers in the cardiac conduction system and (2) a sodium channel (Nav1.5) that regulates the cardiac action potential. The biophysical and biochemical studies in Aims 1 & 2 combine molecular mutagenesis, electrophysiology and phospho-proteomics to investigate how HCN and Nav1.5 are regulated by PI3K signaling. The animal studies in Aims 1 & 2 investigate how reduced PI3K signaling perturbs the function of HCN and Nav1.5 and alters physiology in native cardiac tissues. The high-fat diet experiments to induce insulin resistance will determine whether changes in the activity of Nav1.5 produce cardiac electrophysiological abnormalities in vivo. The clinical study in Aim 3 takes advantage of heart tissue routinely excised during cardiac surgery to test the hypothesis that decreased insulin/PI3K signaling due to insulin resistance is associated with (1) increased persistent sodium current (mediated by Nav1.5) and QT interval prolongation, and (2) reduced pacemaker current (mediated by HCN) in humans. In summary, studies in this proposal will yield important translational results that give us a mechanistic understanding of channelopathies caused by reduced insulin/PI3K signaling accompanied by significant clinical implications for the management of diabetic complications.

随着肥胖症和2型糖尿病发病率和患病率的迅速上升，糖尿病并发症 在美国和全世界造成了沉重的医疗负担。这项建议是基于 胰岛素/PI3K信号调节心脏离子电流的创新想法，以及由 PI3K信号减少与糖尿病致心律失常并发症的发生有关。这项建议 研究PI3K信号如何调节(1)非选择性阳离子通道(HCN)的功能 调节心脏传导系统起搏器的触发和(2)钠通道(NaV1.5)，该通道 调节心脏动作电位。AIMS-1和AIMS-2联合收割机的生物物理和生化研究 分子突变、电生理学和磷酸蛋白质组学研究HCN和NaV1.5是如何 受PI3K信号调节。AIMS 1和2中的动物研究调查了PI3K信号转导信号的减少 HCN和NaV1.5的功能和改变天然心脏组织的生理。高脂饮食实验 诱导胰岛素抵抗将决定NaV1.5活性的变化是否会导致心脏 活体内的电生理异常。Aim 3的临床研究常规利用心脏组织 在心脏手术期间切除，以测试胰岛素导致胰岛素/PI3K信号减少的假设 阻力与(1)持续性钠电流增加(由NaV1.5介导)和QT间期有关 延长，以及(2)减少起搏电流(由HCN介导)。综上所述，这方面的研究 建议将产生重要的翻译结果，使我们对通道病有一个机械性的理解 胰岛素/PI3K信号降低引起的并伴有显著临床意义的处理 糖尿病并发症的风险。