MOLECULAR MECHANISMS OF VENTRICULAR TACHYCARDIA

描述（改编自申请人摘要）：特发性心室性 心动过速（VT）是描述各种形式的VT的通用术语， 发生在无结构性心脏病、代谢或电解质的患者中 异常，或没有长QT综合征。 通过 电生理技术和药理学探针的应用， 在过去的几年中，已经确定了几个不同的机械实体。 十年 两种形式的室性心动过速，阵发性运动诱发的室性心动过速和重复性室性心动过速。 单形性室性心动过速，通常起源于右心室流出道 （RVOT）并存在左束支分支传导阻滞（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，终止与b-受体阻滞剂，维拉帕米，迷走神经操作， 腺苷，并且被认为是由于cAMP介导的触发活性。 申请人假设G蛋白中的分子缺陷 偶联β-肾上腺素能受体信号通路可能导致组成性 由于触发的活性导致细胞内cAMP和VT升高。 这样的 缺陷可能是由存在于细胞起源位点的体细胞突变引起的。 佛蒙特州 提高细胞内cAMP的G蛋白体细胞突变 已经在许多内分泌肿瘤中描述了这种水平。 以来 心肌细胞在心脏发生完成后不分裂，这将 突变必须在子宫内发生 拟议的研究测试了 某些形式的室性心动过速是由躯体 异常刺激心脏cAMP生成的细胞突变 组织中 本研究的具体目的是：（1）鉴定 编码G蛋白和其他cAMP依赖性信号成分的基因 可能导致或促进VT的转导途径;（2）确定 可能被鉴定的新突变的细胞定位;（3） 测试（1）中可能鉴定的突变对它们的影响， 通过转染培养的细胞对cAMP积累的影响;和（4） 通过局部表达突变基因来开发VT的动物模型， 会导致一种致突变表型

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.