Arrhythmia Mechanisms from Inherited and Acquired Caveolin3 Dysregulation of IK1

 描述(申请人提供)：离子通道功能障碍导致后天性和遗传性心律失常综合征的心律失常猝死。一个这样的通道家族包括钾内向整流器Kir2、Kir2.1、Kir2.2和Kir2.3，并在功能上组成IK1。KCNJ2编码心脏离子通道Kir2.1，KNCJ2是IK1的主要成分，KNCJ2功能突变导致LQT7，肾上腺素依赖性功能丧失导致CPVT3。IK1在心力衰竭中下调，并降低了对β-肾上腺素能的敏感性，尽管蛋白质和mRNA水平正常至升高。目前我们所知的空白是在获得性和遗传性心律失常综合征中导致Kir2功能丧失的详细机制。这些机制可能依赖于与作为Kir2.1大分子复合体一部分的其他蛋白质的相互作用或调节，到目前为止还不清楚。在心肌细胞中，小窝以CAV3编码的小窝3的存在为特征，并形成离子通道和受体分子的脂质微区。CAV3的突变可导致离子通道功能障碍，如与LQT9相关的功能障碍，导致心律失常的产生和心脏性猝死。小窝蛋白-3(Caveolin-3，Caveolin-3)在心力衰竭中的表达也下调，小窝结构域也是如此。我们以前研究过CAV3LQT9相关突变，发现由于通道膜表达减少，IK1密度降低。在这项提案中，我们将确定Cav3的机制，无论是来自与LQT9相关的突变，还是通过心力衰竭的获得性重塑，导致IK1的调节失调，并在这些情况下促进心律失常的发生。我们将利用新的和创新的方法，如人诱导的多潜能衍生心肌细胞模型和互补心力衰竭模型。这项建议的总体目标是确定Cav3可以贡献或破坏Kir2.1的大分子复合体的机制，以及对IK1功能的影响，从而导致室性心律失常。我们的长期目标是通过表征和识别与异常IK1相关的心律失常发生的机制，改善遗传性或获得性心律失常患者的治疗选择。有了这一建议的知识，我们将更好地理解Kir2.1异常Cav3引起的心律失常的发病机制。提案中开发的模型也将成为治疗学的宝贵试验台。因此，该提案不仅将推动心律失常研究领域的发展，而且还将允许未来开发针对这种和其他心律失常综合征的治疗选择和治疗方法。

 DESCRIPTION (provided by applicant): Ion channel dysfunction causes arrhythmic sudden death in both acquired and inherited arrhythmia syndromes. One such family of channels include potassium inward rectifier Kir2, Kir2.1, Kir2.2 and Kir2.3, and functionally make up IK1. KCNJ2 encodes the cardiac ion channel Kir2.1, the dominant component of IK1, and loss of function mutations in KNCJ2 causes LQT7 and adrenergic dependent loss of function causes CPVT3. IK1 is down-regulated in heart failure and has decreased beta-adrenergic sensitivity despite normal to increased protein and mRNA levels. The current gap in our knowledge is the detailed mechanisms causing loss of Kir2 function in both acquired and inherited arrhythmia syndromes. These mechanisms may depend on interactions with or regulation by other proteins as part of the Kir2.1 macromolecular complex, heretofore unknown. In cardiac myocytes, caveolae are characterized by the presence of Caveolin-3, encoded by CAV3, and form lipid microdomains for ion channels and receptor molecules. Mutations of CAV3 can cause ion channel dysfunction such as those associated with LQT9, leading to arrhythmia generation, and sudden cardiac death. Caveolin-3 (Cav3) is also down-regulated in heart failure as are caveolar domains. We have previously studied CAV3 LQT9 associated mutations and found that IK1 density is decreased due to decreased channel membrane expression. In this proposal we will determine the mechanism by which Cav3, either from mutations associated with LQT9 or by acquired remodeling in heart failure, causes dysregulation of IK1 and contributes to arrhythmogenesis in these conditions. We will utilize novel and innovative methods such as human induced pluripotent derived cardiac myocyte model and complementary heart failure models. The overall objective for this proposal is to identify the mechanism by which Cav3 can contribute or disrupt the macromolecular complex for Kir2.1 and the effects on IK1 function resulting in ventricular arrhythmias. Our long-term goal is to improve treatment options for individuals with inherited or acquired arrhythmias by characterizing and identifying the mechanisms involved in arrhythmogenesis related to abnormal IK1. With knowledge gained from this proposal, we will better understand the pathogenesis of arrhythmias caused by abnormal Cav3 with Kir2.1. The models developed in the proposal will also serve as a valuable test bed for therapeutics. Thus, the proposal will not only advance the field of arrhythmia research but also allow future development of treatment options and therapeutics for this and other arrhythmia syndromes.