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: 8966666
• 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/8966666
• 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; Health; 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 survival; 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; research study; response; second messenger; small hairpin RNA; targeted treatment; 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）： 获得的长QT综合征（LQTS）是一种可能由药物引起的致命性心脏病，也与糖尿病有关。糖尿病患者与非糖尿病人群的QT延长的患病率更高，而QT延长是糖尿病患者心血管死亡的独立危险因素。癌症治疗的最新进展是开发抑制酪氨酸激酶，磷酸肌醇3-激酶（PI3K）的靶向疗法以及其他在致癌作用中起关键作用的信号分子。酪氨酸激酶抑制剂（TKIS）在诸如慢性髓样白血病等癌症的患者生存率显着提高，现在在临床试验中进行的几种PI3K抑制剂也显示出有希望的抗癌活性。但是，这些药物可能引起LQT。我们研究了这些药物诱导的LQT的起源，并发现令人惊讶的是，延长心脏动作电位持续时间（APD）并非归因于降低了重极化钾电流IKR。取而代之的是，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INA峰）减少了，而持久（持续）钠电流（INAP）增加了。 TKI通过抑制PI3K信号传导引起这些影响。众所周知，糖尿病与包括心脏在内的胰岛素反应组织中的PI3K信号降低有关。因此，我们的主要假设是糖尿病中低心脏PI3K信号传导突出了药物诱导的LQT的风险。我们将使用来自两个糖尿病小鼠模型的肌细胞和心脏，以及胰岛素/PI3K信号通路下调的犬心肌细胞来检验这一假设。相反，我们假设心脏PI3K信号传导的胰岛素激活可以改善药物诱导的LQT。我们提出的研究将确定胰岛素/葡萄糖/钾输注是否会逆转狗体内药物诱导的LQT。最后，我们假设除了调节心肌细胞中作用电位的胰岛素受体外，还有多种酪氨酸激酶。我们将采用药理学和SHRNA策略，以鉴定通过PI3K发出信号以调节APD的犬心肌细胞中的所有酪氨酸激酶。这种全面的方法将有助于靶向涉及癌变的特定激酶的更安全的TKI，同时避免对可能引起LQT的激酶的影响。我们认为，这些拟议的研究的结果将导致发展突破性的预防和治疗策略，以应对这种致命的心脏病。