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 1% 的美国人口。房颤的发病率和患病率随着年龄的增长而增加，影响近 8% 的八旬老人。它是一项重大的公共卫生负担，与较高的死亡率和发病风险相关，包括中风、心力衰竭、栓塞事件、痴呆和生活质量受损。由于AF的分子机制和治疗靶点尚不清楚，目前尚无有效的预防和治疗策略。 该提案的目标是研究线粒体在房颤机制中的作用，并确定预防和治疗的新线粒体靶点。心房心肌的结构和电完整性对于预防 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​​子电流破坏和活性氧生成增加相关的代谢和氧化应激。申请人已经证明受损的线粒体能量学和氧化应激会诱发心律失常和肌细胞损失。线粒体 ATP 敏感钾通道 (mitoKATP) 和解偶联蛋白 (UCP) 的激活可通过减轻氧化应激和保护线粒体生物能来保护心肌细胞。然而，目前尚不清楚线粒体功能障碍是否在房颤的发生和进展中发挥作用。 该提议的中心假设是，线粒体功能障碍在房颤的发生和进展之前，会因能量学和氧化应激受损而导致进行性心房重塑和电不稳定。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 UCP 和 mitoKATP 两条线粒体途径是否在 AF 中被破坏，以及是否可以通过治疗来逆转。这一假设将通过两种不同的动物模型进行测试：a) 肝激酶 B1 蛋白 (LKB1) 受到破坏而发生 AF 的小鼠，b) 心房快速起搏导致发生 AF 的猪。具体目标是： 具体目标 1：确定心房线粒体功能障碍在阵发性 AF 发生和进展中的作用。具体目标 2：研究 mitoKATP 功能障碍是否会导致 AF，以及 mitoKATP 的调节是否会阻止 AF 的发生。具体目标 3：确定 MIM 驱动的氧化应激和线粒体 UCP 在 AF 发生中的作用，并确定 UCP 在预防 AF 中的功效。 该项目提出了一种了解 AF 细胞机制并确定预防和治疗 AF 的新分子靶点的原创方法。我们的最终目标是通过针对房颤的线粒体机制来开发有效的临床干预措施来预防和治疗房颤。线粒体在 AF 机制中的作用的表征将为开发这种使人衰弱的疾病的新疗法提供框架和机会。