Cardiac ubiquitin ligases: regulation and role in modulating cardiac excitation.

摘要 QT间期延长会增加室性心律失常和突发性心律失常的可能性。 心源性死亡虽然已经确定了16个基因导致长QT综合征， 这些突变是罕见的，因此可以占一小部分患者， 恶性室性心律失常最近的全基因组关联研究 确定了五个与QT间期延长相关的位点。这些多态性可能 直接和累积导致QT间期延长，因此导致心脏 心律不齐上述基因座之一位于编码以下基因的基因上游： LITAF在蛋白质周转中起重要作用。本研究的总体目标是 研究LITAF在QT间期调节中的作用。本项目将采用活体 和体外实验方法，包括使用斑马鱼、心脏特异性 在小鼠以及新生和成年兔心肌细胞中敲除LITAF。我们 假设LITAF作为心脏NEDD 4泛素连接酶的调节剂 调节心脏兴奋目标1将探索LITAF的机制， 在体内调节L型钙通道和钠通道（斑马鱼和小鼠）， 而目标2将研究LITAF依赖性调节的机制， 体外电压门控钠和钙通道，以及LITAF对特异性 调节这些通道的NEDD4连接酶。

Abstract A prolonged QT interval increases the likelihood for ventricular arrhythmias and sudden cardiac death. Although 16 genes have been identified in causing long QT syndrome, these mutations are rare and can therefore account for a small percentage of patients with malignant ventricular arrhythmias. Recent genome-wide association studies identified five loci associated with a prolonged QT interval. These polymorphisms may directly and cumulatively contribute to QT interval prolongation and therefore to cardiac arrhythmias. One of the aforementioned loci maps upstream of the gene coding for LITAF, which plays an important role in protein turnover. The overall goal of this study is to investigate the role of LITAF in QT interval regulation. This project will employ in vivo and in vitro experimental approaches including the use of zebrafish, cardiac specific knock out of LITAF in mice, and neonatal and adult rabbit cardiomyocytes. We hypothesize that LITAF acts as a regulator for cardiac NEDD4 ubiquitin ligases modulating cardiac excitation. Aim 1 will explore the mechanisms through which LITAF regulates L-type calcium channels and sodium channels in vivo (zebrafish and mice), whereas Aim 2 will study the mechanisms underlying the LITAF-dependent regulation of voltage-gated sodium and calcium channels in vitro, and LITAF regulation of specific NEDD4 ligases that modulate these channels.