Calcium and MAPKinase Signaling and Structural Remodeling in Atrial Fibrillation

心房颤动中的钙和 MAPK 激酶信号传导及结构重塑

• 批准号: 10394414
• 负责人: J Kevin Donahue
• 金额: $ 83.01万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394414
• 关键词: A kinase anchoring protein; Abbreviations; Ablation; Action Potentials; Address; Adverse event; Affect; Anti-Arrhythmia Agents; Atrial Fibrillation; Automobile Driving; CCL2 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Calcineurin inhibitor; Calcium; Calpain; Caring; Cessation of life; Chest Pain; Clinical; Complication; Congestive Heart Failure; Connexin 43; Connexins; Cytomegalovirus; Data; Dependovirus; Developed Countries; Development; Dilated Cardiomyopathy; Disease; Dominant-Negative Mutation; Dyspnea; EFRAC; EGF gene; Elements; Epidermal Growth Factor; Eye; FOSL2 gene; FOXO1A gene; Fatigue; Future; Gene Transfer; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; HDAC4 gene; Health Care Costs; Heart; Heart Atrium; Heart failure; Hospitalization; Individual; Intervention; Investigation; Left Ventricular Ejection Fraction; Left atrial structure; Left ventricular structure; Lightheadedness; MAP2K1 gene; MAPK1 gene; MAPK8 gene; Methods; Minor; Mitogen-Activated Protein Kinases; Mitogens; Molecular; Mutation; Myocardium; Names; Nodal; Oncogenes; Palpitations; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphotransferases; Polymerase Chain Reaction; Potassium Channel; Preclinical Testing; Probability; Procedures; Protein Kinase; Proteins; Public Health; Rattus; Recording of previous events; Recurrence; Refractory; Regimen; Ribosomal Protein S6 Kinase; Ribosomes; Risk; Role; Signal Pathway; Signal Transduction; Sinus; Stroke; Symptoms; Toxic effect; Transforming Growth Factors; Transgenes; Translating; Translations; Virion; atrioventricular node; base; calmodulin-dependent protein kinase II; clinically relevant; connexin 40; effective therapy; extracellular; fibrosarcoma; gene therapy; genetic inhibitor; heart rhythm; novel; nuclear factors of activated T-cells; osteosarcoma; p38 Mitogen Activated Protein Kinase; porcine model; prevent; promoter; sarcoma; side effect; structural heart disease; success; transcription factor

Atrial fibrillation (AF) is the most common rhythm disturbance in the US and other developed countries. AF significantly affects the lives of the afflicted, causing symptoms that range from palpitations to fatigue, weakness, activity intolerance, stroke, congestive heart failure and death. The impact on public health is substantial, with more than 450,000 hospital admissions per year and $26 billion in healthcare costs. Adding to the problems caused by AF is the lack of safe and effective therapies for this rhythm disorder. Pharmacotherapy for AF has a long history of poor efficacy and potentially lethal side effects. Ablation strategies have made inroads in paroxysmal AF, but they continue to be long, difficult procedures with less than optimal success rates and too frequent adverse events. Ablation does not cure AF. We propose development of gene therapy as a new strategy to eliminate AF. Like many other effective therapies, gene therapy must focus on disease mechanism as a starting point for development. In the case of AF, electrical and structural remodeling are critical elements of the disease mechanism that we aim to reverse. We have previously shown the ability to eliminate the action potential shortening and conduction velocity slowing elements of electrical remodeling with gene transfer of a dominant negative potassium channel mutation and connexins. We recently found partial reversal of structural remodeling with inhibition of the calcium/calmodulin-dependent protein kinase II. In this proposal, we hypothesize that calcium and mitogen activated protein kinase signaling cause AF-related structural remodeling. We explore this hypothesis in a clinically relevant porcine model of atrial fibrillation and heart failure by using molecular methods to correlate signaling pathway activation to structural remodeling and specific drug or genetic blockers of the relevant signaling pathways to more completely connect pathway activation to structural remodeling. To address our hypothesis, we propose 3 aims: (1) to define and prevent AF-related structural remodeling caused by calcineurin overactivity; (2) to evaluate ERK1/2 signaling in AF; (3) to evaluate the effects of multiple signaling pathway blockade on AF-related structural remodeling. Successful completion of our aims will not only identify critical mechanisms driving AF-related structural remodeling, but it will also complete a substantial component of the preclinical testing necessary to translate these investigational agents into clinical therapies.

心房颤动（AF）是美国和其他发达国家最常见的心律失常。AF 严重影响患者的生活，引起从心悸到疲劳的症状， 虚弱、活动不耐受、中风、充血性心力衰竭和死亡。对公共卫生的影响 每年有超过450，000人入院，医疗费用为260亿美元。 除了房颤引起的问题外，还缺乏针对这种节律紊乱的安全有效的治疗方法。 房颤的药物治疗具有疗效差和潜在致命副作用的悠久历史。消融 策略在阵发性房颤中取得了进展，但它们仍然是长期的，困难的程序， 而不是最佳的成功率和太频繁的不良事件。消融不能治愈房颤。我们建议 基因治疗作为一种新的治疗房颤的策略，与许多其他有效的治疗方法一样， 治疗必须以疾病机制为发展的出发点。在AF的情况下，电 和结构重塑是我们旨在逆转的疾病机制的关键要素。我们有 先前显示了消除动作电位缩短和传导速度减慢的能力 显性负性钾通道突变基因转移的电重构要素 和连接蛋白。我们最近发现部分逆转的结构重塑与抑制， 钙/钙调蛋白依赖性蛋白激酶II。在这个提议中，我们假设钙和 丝裂原活化蛋白激酶信号传导引起AF相关的结构重塑。我们探索这个 应用分子生物学技术在临床相关猪房颤和心力衰竭模型中的假设 将信号传导途径活化与结构重塑和特定药物或遗传物质相关联的方法 相关信号传导通路的阻断剂，以更完全地将通路激活与结构 重塑为了解决我们的假设，我们提出了3个目标：（1）定义和预防AF相关 钙调神经磷酸酶过度激活引起的结构重构;（2）评估AF中的ERK 1/2信号传导;（3） 评价多信号通路阻断对AF相关结构重构的影响。 成功完成我们的目标不仅将确定驱动AF相关结构的关键机制， 重塑，但它也将完成必要的临床前测试的实质性组成部分， 将这些研究药物用于临床治疗。