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

基本信息

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
项目类别：
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

项目摘要

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紊乱。 AF 严重影响患者的生活，导致心悸、疲劳等症状，虚弱、活动不耐受、中风、充血性心力衰竭和死亡。对公众健康的影响是每年住院人数超过 450,000 人，医疗费用高达 260 亿美元。房颤造成的问题更为严重的是，缺乏针对这种节律紊乱的安全有效的治疗方法。房颤药物治疗长期以来一直疗效不佳，并有潜在致命的副作用。消融策略已在阵发性房颤治疗中取得了进展，但它们仍然是一个漫长、困难的过程，且效果较差。低于最佳成功率和过于频繁的不良事件。消融不能治愈 AF。我们建议基因疗法的发展作为消除房颤的新策略。与许多其他有效疗法一样，基因疗法治疗必须围绕疾病机制作为发展的起点。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。我们有先前显示出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塑要素和连接蛋白。我们最近发现结构重塑的部分逆转与抑制钙/钙调蛋白依赖性蛋白激酶 II。在这个提议中，我们假设钙和有丝分裂原激活的蛋白激酶信号传导导致 AF 相关的结构重塑。我们探索这个通过使用分子技术在临床相关的猪心房颤动和心力衰竭模型中提出假设将信号通路激活与结构重塑和特定药物或遗传相关联的方法相关信号传导途径的阻断剂，以更完整地将途径激活与结构联系起来重塑。为了解决我们的假设，我们提出 3 个目标：(1) 定义和预防 AF 相关疾病钙调神经磷酸酶过度活性引起的结构重塑； (2) 评估 AF 中的 ERK1/2 信号传导； (3) 评估多重信号通路阻断对房颤相关结构重塑的影响。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，但它也将完成转化所需的临床前测试的重要组成部分这些研究药物进入临床治疗。