Micropeptide Control of Cardiac Rhythm

项目总结/摘要 心律失常是成人发病的主要原因，可导致心源性猝死， 死亡的主要原因。心脏是一个机电泵，它依赖于电压门控 钾（K+）通道（VGKCs）和K+调节蛋白以维持正常的心律和收缩性。 人类电压门控K+通道和K+调节蛋白的突变与心律失常有关， 晕厥和猝死疾病相关基因和变异体的鉴定代表了一种 这对心血管疾病的早期诊断和治疗提出了重大挑战。 最近，我们发现了一个小的心脏富集的跨膜微肽编码的一个小的开放 我们将其命名为KCNEmini的阅读框架，这是由于其序列和结构与 KCNE系列VGKC调节器。初步研究表明KCNEmini与VGKCS共定位 并在基于细胞的测定中作为K+通道hERG的新型调节剂发挥作用。有趣的是， KCNEmini在小鼠中导致QT间期延长和心脏肥大。在这个应用程序中，我们将 确定KCNEmini的功能：作为心脏电压门控K+通道的直接调节剂， 电生理学和基于细胞的实验（目的1），其在控制心脏节律中的作用，使用新的 KCNEmini基因敲除小鼠体内（目的2），及其减轻病理性电和细胞损伤的潜力 心脏肥大引起的重塑（目的3）。这些研究将阐明 一种以前未被认识到的心脏K+处理调节剂，可能是未来重要的治疗药物。 致死性心律失常的诊断和治疗靶点。 !

Project Summary/Abstract Cardiac arrhythmias are the leading cause of morbidity in adults and can result in sudden cardiac death, a leading cause of mortality. The heart is an electromechanical pump which depends on voltage-gated potassium (K+) channels (VGKCs) and K+ regulatory proteins to maintain normal heart rhythm and contractility. Human mutations in voltage-gated K+ channels and K+ regulatory proteins are associated with arrhythmias, syncope, and sudden death. The identification of disease-associated genes and variants represents a significant challenge towards the early diagnosis and treatment of arrhythmogenic cardiovascular diseases. Recently, we discovered a small cardiac-enriched transmembrane micropeptide encoded by a small open reading frame which we named KCNEmini, due to its sequence and structural homology with members of the KCNE family of VGKC regulators. Preliminary studies have shown that KCNEmini co-localizes with VGKCS and functions as a novel regulator of the K+ channel hERG in cell-based assays. Interestingly, disruption of KCNEmini in mice results in QT interval prolongation and cardiac hypertrophy. In this application we will determine the function of KCNEmini: as a direct regulator of cardiac voltage-gated K+ channels using electrophysiology and cell-based experiments (Aim 1), its role in controlling cardiac rhythm using novel KCNEmini knockout mice in vivo (Aim 2), and its potential to mitigate the pathological electrical and cellular remodeling that occurs in response to cardiac hypertrophy (Aim 3). These studies will shed light on the role of a previously unrecognized regulator of K+ handling in the heart, which may be an important future therapeutic target for the diagnosis and treatment of lethal cardiac rhythm disorders. !