PI3K signaling and channelopathies in the heart

随着肥胖和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沉重的医疗负担。这项建议是根据 胰岛素/PI 3 K信号传导调节心脏中的离子电流的创新想法，以及由胰岛素/PI 3 K信号传导引起的通道病。 减少的PI 3 K信号传导有助于糖尿病致糖尿病并发症的发展。该提案 研究PI 3 K信号传导如何调节（1）非选择性阳离子通道（HCN）的功能， 调节心脏传导系统中起搏器的放电，以及（2）钠通道（Nav1.5）， 调节心脏动作电位。目标1和2联合收割机的生物物理和生物化学研究 分子诱变，电生理学和磷酸化蛋白质组学来研究HCN和Nav1.5是如何被 由PI 3 K信号调节。目的1和2中的动物研究研究了减少的PI 3 K信号传导如何干扰 HCN和Nav1.5的功能并改变天然心脏组织中的生理学。高脂饮食实验 诱导胰岛素抵抗将决定Nav1.5活性的变化是否产生心脏功能， 体内电生理异常。Aim 3中的临床研究常规利用心脏组织 在心脏手术期间切除，以测试由于胰岛素引起的胰岛素/PI 3 K信号传导减少的假设。 耐药与（1）持续钠电流（由Nav1.5介导）和QT间期增加有关 延长，和（2）减少起搏器电流（由HCN介导）。总之，这方面的研究 该提案将产生重要的翻译结果，使我们对通道病有一个机械的理解 由胰岛素/PI 3 K信号传导减少引起，伴随着对管理的重大临床意义 糖尿病并发症

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.