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：
10604289
负责人：
J Kevin Donahue
金额：
$ 83.17万
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/10604289
关键词：
A kinase anchoring protein Abbreviations Ablation Acceleration 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 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 Paint Palpitations Pathway interactions Patients Pharmaceutical Preparations 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 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 pharmacologic 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节奏扰动。 AF 显着影响受苦的生活的生活，导致症状，从心per到疲劳，弱点，活动不耐受，中风，充血性心力衰竭和死亡。对公共卫生的影响是实质性，每年有超过450,000次住院和260亿美元的医疗保健费用。除了AF引起的问题外，还缺乏这种节奏障碍的安全有效疗法。 AF的药物疗法的功效不良和潜在致命的副作用的史。消融策略在阵发性AF中脱颖而出，但它们仍然是漫长而艰难的程序，较少比最佳成功率和过于频繁的不良事件。消融无法治愈AF。我们建议开发基因疗法作为消除AF的新策略。像许多其他有效的疗法一样，基因治疗必须集中于疾病机制，作为发展的起点。对于AF，电气结构重塑是我们旨在逆转的疾病机制的关键要素。我们有先前显示的能够消除动作电位缩短和传导速度放缓的能力用显性负钾通道突变的基因转移电气重塑的元素和连接素。我们最近发现结构重塑的部分逆转并抑制钙/钙调蛋白依赖性蛋白激酶II。在此提案中，我们假设钙和有丝分裂激活的蛋白激酶信号传导引起与AF相关的结构重塑。我们探索这个通过使用分子，在临床相关的房颤和心力衰竭的临床相关猪模型中假设将激活信号通路与结构重塑和特定药物或遗传相关的方法相关信号通路的阻滞剂，以更完整地将途径激活连接到结构重塑。为了解决我们的假设，我们提出了3个目标：（1）定义和防止与AF有关由钙调神经蛋白过度活跃引起的结构重塑；（2）评估AF中的ERK1/2信号传导；（3）评估多个信号通路阻断对与AF相关的结构重塑的影响。成功完成我们的目标不仅会确定驱动与自动自动股AF相关结构的关键机制重塑，但它也将完成翻译所需的临床前测试的重要组成部分这些研究剂对临床疗法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Atrial Gene Painting in Large Animal Model of Atrial Fibrillation.

心房颤动大型动物模型中的心房基因绘制。

DOI：
10.1007/978-1-0716-2707-5_16
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Mo,Weilan;Donahue,JKevin
通讯作者：
Donahue,JKevin

Preclinical safety and biodistribution assessment of Ad-KCNH2-G628S administered via atrial painting in New Zealand white rabbits.

Ad-KCNH2-G628S 通过新西兰白兔心房涂敷给药的临床前安全性和生物分布评估。

DOI：
10.1111/bcpt.13885
发表时间：
2023
期刊：
Basic & clinical pharmacology & toxicology
影响因子：
3.1
作者：
Benson,JanetM;Wang,Gensheng;Hutt,JulieA;Wu,Guodong;Kaminsky,StephenM;Cram,Sara;Barur,Rajeshkumar;Donahue,JKevin
通讯作者：
Donahue,JKevin