Decreased PI3K Signaling and Long QT Syndrome in Diabetes

糖尿病患者 PI3K 信号传导减弱和长 QT 综合征

• 批准号: 8544539
• 负责人: RICHARD Z LIN
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544539
• 关键词: Action Potentials; Adult; Adverse effects; Antihistamines; Arrhythmia; Canis familiaris; Cardiac; Cardiac Myocytes; Cessation of life; Chronic Myeloid Leukemia; Cisapride; Clinical Trials; Culture Media; Dasatinib; Development; Diabetes Mellitus; Diabetic mouse; Dose; Exhibits; Glucose; Heart; Heart Block; Heart Rate; Incidence; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Lead; Lipids; Long QT Syndrome; Malignant Neoplasms; Mammals; Measurement; Measures; Modeling; Muscle Cells; Patch-Clamp Techniques; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Play; Population; Potassium; Prevalence; Preventive; Protein Tyrosine Kinase; Reporting; Risk; Role; Safety; Science; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Sodium; Terfenadine; Testing; Therapeutic; Tissues; Tyrosine Kinase Inhibitor; Ventricular; Work; cancer therapy; carcinogenesis; cardiovascular risk factor; design; diabetic; diabetic patient; dofetilide; improved; in vivo; inhibitor/antagonist; insulin signaling; kinase inhibitor; mouse model; mutant; non-diabetic; patch clamp; phosphatidylinositol 3,4,5-triphosphate; prevent; public health relevance; research study; response; second messenger; small hairpin RNA; translational medicine

DESCRIPTION (provided by applicant): Acquired long QT syndrome (LQTS) is a potentially lethal cardiac condition that can be caused by medications and is also associated with diabetes mellitus. The prevalence of QT prolongation is higher in the diabetic vs. the non-diabetic population, and QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. A major recent advance in cancer treatment has been the development of targeted therapies that inhibit tyrosine kinases, phosphoinositide 3-kinases (PI3Ks), and other signaling molecules that play critical roles in carcinogenesis. Tyrosine kinase inhibitors (TKIs) have significantly improved patient survival for cancers such as chronic myeloid leukemia, and several PI3K inhibitors now in clinical trials also show promising anti-cancer activity. However, these drugs can cause LQTS. We investigated the origins of the LQTS induced by these drugs and discovered to our surprise that prolongation of the cardiac action potential duration (APD) was not due uniquely to a reduction in the repolarizing potassium current, IKr. Instead, as we recently reported in Science Translational Medicine, multiple currents (IKr, IKs, ICaL, and peak INa) were reduced, while long-lasting (persistent) sodium current (INaP) was increased. TKIs caused these effects by inhibiting PI3K signaling. It is well established that diabetes mellitus is associated with decreased PI3K signaling in insulin- responsive tissues, including the heart. Therefore, our main hypothesis is that low cardiac PI3K signaling in diabetes accentuates the risk of drug-induced LQTS. We will test this hypothesis using myocytes and hearts from two diabetic mouse models, as well as canine myocytes in which the insulin/PI3K signaling pathway is down-regulated. Conversely, we hypothesize that insulin activation of cardiac PI3K signaling ameliorates drug- induced LQTS. Our proposed studies will determine whether insulin/glucose/potassium infusion reverses drug- induced LQTS in vivo in dogs. Lastly, we hypothesize that there are multiple tyrosine kinases in addition to the insulin receptor that regulate the action potential in cardiac myocytes. We will us pharmacologic and shRNA strategies to identify all of the tyrosine kinases in canine cardiac myocytes that signal through PI3K to regulate the APD. This comprehensive approach will facilitate the development of safer TKIs that target specific kinases involved in carcinogenesis while avoiding effects on kinases that could cause LQTS. We believe that results from these proposed studies will lead to the development of breakthrough preventive and therapeutic strategies to counter this deadly cardiac condition.

描述（由申请人提供）： 获得性长 QT 综合征 (LQTS) 是一种潜在致命的心脏病，可由药物引起，也与糖尿病有关。与非糖尿病人群相比，糖尿病人群QT间期延长的发生率更高，并且QT间期延长是糖尿病患者心血管死亡的独立危险因素。癌症治疗的最新重大进展是开发了抑制酪氨酸激酶、磷酸肌醇 3-激酶 (PI3K) 和其他在癌发生中发挥关键作用的信号分子的靶向疗法。酪氨酸激酶抑制剂 (TKI) 显着提高了慢性粒细胞白血病等癌症患者的生存率，目前正在进行临床试验的几种 PI3K 抑制剂也显示出有希望的抗癌活性。然而，这些药物可引起 LQTS。我们研究了这些药物诱导的 LQTS 的起源，并惊讶地发现心脏动作电位持续时间 (APD) 的延长并不是唯一由复极化钾电流 IKr 的减少引起的。相反，正如我们最近在《科学转化医学》中报道的那样，多种电流（IKr、IKs、ICaL 和峰值 INa）减少，而持久（持续）钠电流 (INaP) 增加。 TKI 通过抑制 PI3K 信号传导引起这些效应。众所周知，糖尿病与胰岛素反应性组织（包括心脏）中 PI3K 信号传导减少有关。因此，我们的主要假设是，糖尿病患者心脏 PI3K 信号传导水平较低会加剧药物引起的 LQTS 风险。我们将使用来自两种糖尿病小鼠模型的肌细胞和心脏，以及胰岛素/PI3K信号通路下调的犬肌细胞来检验这一假设。相反，我们假设胰岛素激活心脏 PI3K 信号传导可改善药物诱导的 LQTS。我们提出的研究将确定胰岛素/葡萄糖/钾输注是否可以逆转狗体内药物诱导的 LQTS。最后，我们假设除了胰岛素受体之外还有多种酪氨酸激酶调节心肌细胞的动作电位。我们将使用药理学和 shRNA 策略来识别犬心肌细胞中通过 PI3K 发出信号来调节 APD 的所有酪氨酸激酶。这种综合方法将促进更安全的 TKI 的开发，这些 TKI 靶向参与致癌作用的特定激酶，同时避免对可能导致 LQTS 的激酶产生影响。我们相信，这些拟议研究的结果将导致突破性预防和治疗策略的发展，以对抗这种致命的心脏病。