Unfolded Protein Response and Arrhythmias

未折叠的蛋白质反应和心律失常

• 批准号: 9977253
• 负责人: SAMUEL C DUDLEY
• 金额: $ 47.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977253
• 关键词: ATF6 gene; Action Potentials; Affect; Animal Model; Arrhythmia; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; Data; Down-Regulation; Endoplasmic Reticulum; Epidemic; Estrogen receptor positive; Event; Genes; Genetic; Genetic Transcription; Heart failure; Human; Infarction; Inositol; Ion Channel; Knock-out; Left Ventricular Dysfunction; Link; Mediating; Membrane; Messenger RNA; Mink; Modeling; Molecular Chaperones; Mus; Myocardial Infarction; Myocardial Ischemia; Passive Ion Transport; Pharmacology; Phosphorylation; Phosphotransferases; Population; Potassium Channel; Prevention; Protein Kinase; Proteins; Risk; Scheme; Signal Transduction; Sudden Death; Testing; Translations; Ventricular; Ventricular Tachycardia; activating transcription factor; endoplasmic reticulum stress; glucose-regulated proteins; improved; in vivo; indium arsenide; induced pluripotent stem cell; ischemic cardiomyopathy; mRNA Decay; novel therapeutics; prevent; protein activation; protein folding; response; sensor; sudden cardiac death; treatment strategy

Project Summary Altered membrane currents are implicated in sudden cardiac death. Ischemic cardiomyopathy (ICM) is responsible for three quarters of these deaths. In preliminary data, we show that (i) PERK, part of the unfolded protein response (UPR), is activated early and persistently in a mouse myocardial infarct (MI) model, (ii) inhibiting PERK after MI reduces sudden death, reduces spontaneous, nonsustained ventricular tachycardia (VT), reduces QTc interval, and reduces action potential duration (APD) without negative consequences to contractile function, (iii) the UPR activation prolongs APD, slows AP upstroke, and alters some but not all ion channels, and (iv) PERK inhibition partially reversed APD prolongation and some ion channel downregulations. Hypothesis: We hypothesize that activation of PERK and other UPR sensors reduce mRNA abundance and protein translation of cardiac ion channels. This contributes to current alterations, APD prolongation, and increased arrhythmic risk in ICM. Inhibition of PERK or other UPR effectors can prevent some of the remodeling. In vivo, PERK inhibition will be antiarrhythmic in ICM, in part, by improving conduction velocity and reducing APD. Specific aims: Aim 1: Determine the extent to which PERK inhibition can prevent APD prolongation, electrical remodeling and arrhythmic risk associated with ICM. In this aim, ICM will be induced in mice. APD, electrical remodeling and arrhythmic risk will be compared between mice with and without pharmacological inhibition of PERK starting immediate after infarct or at 3 weeks to test prevention versus treatment strategies. Results will be compared to genetic inhibition of PERK (cardiac specific PERK-knockout (KO)) and to findings in human ICM. Aim 2: Determine the extent to which PERK can contribute to APD prolongation and the alterations of ion channels. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with activated UPR, we will determine which other ion channels are altered by UPR and PERK activation and are responsible for APD prolongation. Aim 3: Investigate whether the IRE1 and ATF6 branches of the UPR contribute to APD prolongation and the alterations of ion channels. Using hiPSC-CMs and activating the IRE1 and ATF6 branches of UPR, we will determine whether activation of these two branches contributes to AP changes and downregulation of cardiac ion channels.

项目概要 膜电流的改变与心源性猝死有关。缺血性心肌病（ICM）是 造成四分之三死亡的原因。在初步数据中，我们表明 (i) PERK，展开的一部分 蛋白质反应 (UPR) 在小鼠心肌梗塞 (MI) 模型中早期且持续激活，(ii) MI 后抑制 PERK 可减少猝死，减少自发性、非持续性室性心动过速 (VT)，缩短 QTc 间期，并缩短动作电位持续时间 (APD)，而不会产生负面影响 收缩功能，(iii) UPR 激活延长 APD，减慢 AP 上冲程，并改变一些但不是全部离子 (iv) PERK 抑制部分逆转 APD 延长和一些离子通道下调。 假设：我们假设 PERK 和其他 UPR 传感器的激活会降低 mRNA 丰度， 心脏离子通道的蛋白质翻译。这有助于电流改变、APD 延长和 ICM 中心律失常的风险增加。抑制 PERK 或其他 UPR 效应子可以防止某些 重塑。在体内，PERK 抑制将在 ICM 中具有抗心律失常作用，部分原因是通过提高传导速度和 减少 APD。 具体目标： 目标 1：确定 PERK 抑制可在多大程度上防止 APD 延长、电 与 ICM 相关的重构和心律失常风险。为此，将在小鼠中诱导 ICM。阿帕德, 将比较接受和不接受药物治疗的小鼠之间的电重构和心律失常风险 梗死后立即或 3 周后开始抑制 PERK，以测试预防策略与治疗策略。 结果将与 PERK 基因抑制（心脏特异性 PERK 敲除 (KO)）和研究结果进行比较 在人类 ICM 中。 目标 2：确定 PERK 对 APD 延长和改变的影响程度 离子通道。使用人类诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 并激活 UPR，我们将确定哪些其他离子通道因 UPR 和 PERK 激活而改变并负责 用于 APD 延长。 目标 3：研究 UPR 的 IRE1 和 ATF6 分支是否有助于 APD 延长 以及离子通道的改变。使用 hiPSC-CM 并激活 IRE1 和 ATF6 分支 UPR，我们将确定这两个分支的激活是否会导致 AP 变化以及 心脏离子通道的下调。