Molecular Mechanisms for Atrial Fibrillation in Aging

衰老过程中心房颤动的分子机制

• 批准号: 9201766
• 负责人: Sami Fouad Noujaim
• 金额: $ 38.33万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201766
• 关键词: Molecular; Mechanisms; Atrial; Fibrillation; Aging

PROJECT SUMMARY In clinical practice, atrial fibrillation (AF) is the most common heart rhythm disturbance, and a major cause of morbidity and mortality. The incidence of AF increases greatly with age, and given the aging of our overall population, its prevalence is rising at alarming rates. Yet the treatment of AF remains inadequate due in part to our relatively poor understanding of AF pathoelectrophysiology. In this application, we propose to focus on aging mediated AF. The goal is to investigate previously unexplored direct mechanistic links between aging, oxidative stress, the acetylcholine sensitive inward rectifier potassium current IKACh, and AF. We will test the hypothesis that the increased oxidative stress in aged atria activates PKCepsilon, which in turn phosphorylates Kir3.1- a molecular correlate of IKACh, leading to muscarinic stimulation independent constitutively active IKACh, shortening of action potential duration, and AF perpetuation. Our preliminary data support our hypothesis and show that: 1-) aging promotes the phosphorylation of Kir3.1 and leads to the constitutive activation of IKACh, 2-) oxidative stress activates PKCepsilon, phosphorylates Kir3.1, and shortens the atrial action potential due to a constitutively active IKACh, and facilitates the development of rotors responsible for AF, and 3)- phosphorylation of Kir3.1 initiates conformational changes which could increase the channel's interaction with its activator PIP2, and result in the opening of the channel's intracellular ion permeation pathway. We will test our hypothesis in 3 specific aims: 1-) To investigate the molecular and signaling pathways leading to constitutively active IKACh in aging, through oxidative stress and PKCepsilon mediated Kir3.1 phosphorylation; 2-) To determine the structural changes that occur in Kir3.1 phosphorylated by PKCepsilon, with X-ray crystallography and molecular dynamics simulations; and 3-) To study the role of aging, PKCepsilon and constitutively active IKACh in the inducibility and dynamics of atrial fibrillation. We will make simultaneous use of several complementary and powerful techniques (X-ray crystallography, molecular modeling, molecular biology, single cell, and whole organ electrophysiology) to test our aims and to investigate from the protein structure, to the multicellular level, the details of how aging modifies the structure and function of an ion channel, leading to proarrhythmic electrical changes in the atria. We postulate that the studies proposed will increase our understanding of AF pathoelectrophysiology, and could direct the identification of antifibrillatory pathway targets, and the development of novel, specific, and effective anti-atrial fibrillation agents.

在临床实践中，心房颤动（AF）是最常见的心律失常， 也是发病率和死亡率的主要原因。房颤的发病率随着年龄的增长而大大增加， 由于本港整体人口老化，其发病率正以惊人的速度上升。然而，房颤的治疗仍然是 部分原因是我们对AF病理电生理学的理解相对较差。在本申请中， 我们建议关注衰老介导的AF。目标是研究以前未探索的直接机制， 衰老、氧化应激、乙酰胆碱敏感性内向整流钾电流IKACh和 AF.我们将检验这一假设，即老年心房氧化应激增加激活PKC β， 将磷酸化Kir3.1-IKACh的分子相关物，导致毒蕈碱刺激独立 组成性激活IKACh、缩短动作电位时程和AF永久化。我们的初步数据 支持我们的假设，并表明：1-）老化促进Kir3.1的磷酸化，并导致 IKACh的组成性激活，2-）氧化应激激活PKC β，磷酸化Kir3.1，并缩短 心房动作电位由于组成性活动IKACh，并促进转子的发展 3）Kir3.1的磷酸化引发构象变化，这可能增加AF的发生。 通道与其激活剂PIP 2的相互作用，并导致通道的细胞内离子的开放 渗透途径我们将在3个具体目标中测试我们的假设：1-）研究分子和 通过氧化应激和PKC β 2介导衰老中IKACh的信号通路 2-）为了确定Kir3.1磷酸化的细胞中发生的结构变化， 通过PKC 13，X射线晶体学和分子动力学模拟;和3-）研究 年龄、PKC β和组成性激活IKACh在心房颤动的诱导和动力学中的作用。我们将 同时使用几种互补和强大的技术（X射线晶体学，分子 建模，分子生物学，单细胞和整个器官电生理学）来测试我们的目标和研究 从蛋白质结构到多细胞水平，衰老如何改变结构和功能的细节 离子通道的作用，导致心房的促心律变化。我们假设这些研究 提出的方法将增加我们对房颤病理电生理学的了解，并可以指导房颤的识别 抗心房颤动通路靶点，以及新型、特异性和有效抗心房颤动药物的开发 剂.