MOLECULAR MECHANISMS OF VENTRICULAR TACHYCARDIA

描述(改编自申请人的摘要)：特发性脑室 心动过速(VT)是一个通用术语，描述各种形式的VT 发生于无结构性心脏病、代谢或电解质的患者 异常，或在没有长QT综合征的情况下。通过 电生理技术和药理探针的应用， 在过去的一年中，已经确定了几个不同的机械实体 十年。阵发性运动性室速和重复性室性心动过速两种形式 单形性室速，通常起源于右室流出道 (RVOT)，并伴有左束支传导阻滞(LBBB)下轴 形态学。这些心动过速是由细胞内钙离子介导的。 超负荷使用b-受体阻滞剂、维拉帕米、迷走神经和 腺苷，被认为是由于cAMP介导的触发活动。 申请人假设G蛋白中的一个分子缺陷 偶联b-肾上腺素能受体信号通路可能导致结构性 触发活动导致细胞内cAMP和VT升高。这样的一个 缺陷可能源于起源地存在的体细胞突变。 VT.G蛋白的体细胞突变导致细胞内cAMP升高 在一些内分泌肿瘤中已经描述了这种水平。自.以来 心肌细胞在心脏生成完成后不会分裂，这将 有必要使突变发生在子宫内。拟议的研究测试了 某些形式的室性心动过速源于躯体的假说 异常刺激心脏cAMP生成的细胞突变 纸巾。这项建议的具体目标是：(1)确定 编码G蛋白和cAMP依赖信号的其他成分的基因 可能导致或促进室性心动过速的转导途径；(2)确定 可能被识别的新突变的细胞定位；(3) 测试可在(1)中确定的突变对其影响 转染法对培养细胞内cAMP积聚的影响； 通过局部表达突变基因建立VT的动物模型 可以预测会导致心律失常的表型。

DESCRIPTION (adapted from the applicant's abstract): Idiopathic ventricular tachycardia (VT) is a generic term that describes various forms of VT that occur in patients without structural heart disease, metabolic or electrolyte abnormalities, or in the absence of the long QT syndrome. Through the application of electrophysiologic techniques and pharmacological probes, several distinct mechanistic entities have been identified in the last decade. Two forms of VT, paroxysmal exercise-induced VT and repetitive monomorphic VT, typically originate from the right ventricular outflow tract (RVOT) and present with a left bundle branch block (LBBB) inferior axis morphology. These tachycardias are mediated by intracellular calcium overload and terminate with b-blockers, verapamil, vagal maneuvers and adenosine, and are thought to be due to cAMP-mediated triggered activity. The applicant hypothesizes that a molecular defect in the G protein coupled-b-adrenergic receptor signaling pathway might result in constitutive elevation of intracellular cAMP and VT due to triggered activity. Such a defect could arise from a somatic mutation present at the site of origin of VT. Somatic cell mutations in G proteins that elevate intracellular cAMP levels have been described in a number of endocrine tumors. Since myocardial cells do not divide after cardiogenesis is complete, this would necessitate that the mutation occur in utero. The proposed studies test the hypothesis that certain forms of ventricular tachycardia arise from somatic cell mutations which abnormally stimulate cAMP generation in cardiac tissues. Specific Aims of this proposal are: (1) To identify mutations in genes encoding G proteins and other components of cAMP-dependent signal transduction pathways that might cause or facilitate VT; (2) To determine the cellular localization of new mutations that might be identified; (3) To test the effects of mutations which may be identified in (1) for their effects on cAMP accumulation by transfection of cells in culture; and (4) To develop an animal model for VT by locally expressing mutant genes which we would predict to confer an arrhythmogenic phenotype.