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: 8762239
• 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/8762239
• 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; 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.

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