Mitochondrial Mechanisms and Novel Therapeutic Targets in Atrial Fibrillation

心房颤动的线粒体机制和新治疗靶点

• 批准号: 8700954
• 负责人: Cevher Ozcan
• 金额: $ 15.31万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700954
• 关键词: ATP sensitive potassium channel complex; Admission activity; Affect; Age; American; Animal Model; Arrhythmia; Atrial Fibrillation; Attenuated; Bioenergetics; Biological Preservation; Calcium-Activated Potassium Channel; Cardiac Myocytes; Cessation of life; Clinical; Complex; Dementia; Development; Disease; Event; Family suidae; Fibrosis; Functional disorder; Generations; Goals; Heart Atrium; Heart failure; Homeostasis; Hospitals; Incidence; Injury; Inner mitochondrial membrane; Ion Channel; Membrane Potentials; Membrane Structure and Function; Metabolic stress; Mitochondria; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardium; Octogenarian; Oxidative Stress; Pathway interactions; Play; Population; Prevalence; Prevention; Prevention strategy; Prevention therapy; Preventive Intervention; Proteins; Public Health; Quality of life; Reactive Oxygen Species; Refractory; Research Personnel; Risk; Role; STK11 gene; Sinus; Stretching; Stroke; Testing; Transgenic Mice; Translating; Work; disability; gene therapy; heart rhythm; high risk; mitochondrial K(ATP) channel; mitochondrial dysfunction; mortality; muscle form; new therapeutic target; novel; pre-clinical; prevent; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common heart rhythm disease and affects 1% of the US population. The incidence and prevalence of AF rise with age to affect nearly 8% of octogenarians. It is a major public health burden and associated with higher risks of mortality and morbidity including stroke, heart failure, embolic events, dementia and impaired quality of life. There is no effective strategy for the prevention and treatment of AF since the molecular mechanisms and the mechanistic therapeutic targets are not known. The goal of this proposal is to investigate the role of mitochondria in the mechanisms of AF and to define the novel mitochondrial targets for prevention and treatment. The structural and electrical integrity of atrial myocardium is essential for prevention of AF and that is dependent upon normal mitochondrial function. Mitochondrial dysfunction causes metabolic and oxidative stress in association with ATP depletion, disruption of ionic currents and increased reactive oxygen species generation. The applicant has demonstrated that impaired mitochondrial energetics and oxidative stress induce arrhythmias and myocyte loss. Activation of mitochondrial ATP-sensitive potassium channel (mitoKATP) and uncoupling proteins (UCP) protect cardiomyocytes by attenuating oxidative stress and preserving mitochondrial bioenergetics. However, it is unclear as to whether mitochondrial dysfunction plays a role in the development and progression of AF. The central hypothesis of this proposal is that mitochondrial dysfunction precedes the initiation and the progression of AF by causing progressive atrial remodeling and electrical instability due to impaired energetics and oxidative stress. To test this, we will evaluate the molecular and cellular changes associated with the onset of AF, and determine whether two mitochondrial pathways UCP and mitoKATP are disrupted in AF, and whether they can be reversed with therapy. This hypothesis will be tested by using two distinct animal models: a) mice with disruption of the liver kinase B1 protein (LKB1) that develop AF, and b) pigs with rapid atrial pacing that develop AF. The Specific Aims are: Specific Aim 1: Determine the role of atrial mitochondrial dysfunction in the onset and progression of paroxysmal AF. Specific Aim 2: Investigate whether mitoKATP dysfunction causes AF and whether modulation of mitoKATP prevents the development of AF. Specific Aim 3: Determine the role of MIM-driven oxidative stress and mitochondrial UCPs in the development of AF and identify the efficacy of UCPs in prevention of AF. This project presents an original approach for understanding the cellular mechanisms of AF and identifying the novel molecular targets for the prevention and treatment of AF. Our ultimate goal is to develop effective clinical interventions for the prevention and treatment of AF by targeting mitochondrial mechanisms of AF. Characterization of the role of mitochondria in the mechanism of AF will provide a framework and an opportunity to develop novel therapies for this debilitating disease.

描述（由申请人提供）：心房颤动（AF）是最常见的心律疾病，影响了1％的美国人群。 AF随着年龄的增长的发病率和流行率会影响近8％的八十岁人。这是一个主要的公共卫生负担，与较高的死亡率和发病率风险有关，包括中风，心力衰竭，栓塞事件，痴呆症和生活质量受损。由于分子机制和机械治疗靶标的是预防和治疗AF的有效策略。 该提案的目的是研究线粒体在AF机制中的作用，并定义新的线粒体预防和治疗目标。心房心肌的结构和电气完整性对于预防AF至关重要，这取决于正常的线粒体功能。线粒体功能障碍会导致与ATP耗竭，离子电流的破坏以及活性氧的产生增加的代谢和氧化应激。申请人表明，线粒体能量和氧化应激受损会诱导心律不齐和心肌损失。线粒体ATP敏感的钾通道（MitokATP）的激活和解偶联蛋白（UCP）通过减轻氧化应激并保留线粒体生物能力来保护心肌细胞。但是，目前尚不清楚线粒体功能障碍是否在AF的发展和发展中起作用。 该提议的中心假设是，线粒体功能障碍是通过引起渐进性心房重塑和由于能量受损和氧化应激而引起的渐进性心房重塑和电不稳定性的前进和进展。为了测试这一点，我们将评估与AF发作相关的分子和细胞变化，并确定在AF中是否破坏了两种线粒体途径UCP和MitokATP，以及它们是否可以通过治疗逆转。该假设将通过使用两种不同的动物模型来检验：a）肝激酶B1蛋白（LKB1）的小鼠会产生AF，b）猪具有快速心房起搏的猪会产生AF。具体目的是：具体目标1：确定心房功能障碍在阵发性AF的发作和进展中的作用。具体目标2：研究MitokATP功能障碍是否导致AF以及MitokATP的调节是否阻止了AF的发展。具体目标3：确定MIM驱动的氧化应激和线粒体UCP在AF发展中的作用，并确定UCPS预防AF的功效。 该项目提出了一种理解AF的细胞机制的原始方法，并确定了预防和治疗AF的新型分子靶标。我们的最终目标是通过靶向AF的线粒体机制来开发有效的临床干预措施，以预防和治疗AF。线粒体在AF机制中的作用的表征将为这种使人衰弱的疾病开发新疗法提供框架和机会。