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:
- 金额:$ 83.01万
- 依托单位:
- 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:
- 关键词:A kinase anchoring proteinAbbreviationsAblationAction PotentialsAddressAdverse eventAffectAnti-Arrhythmia AgentsAtrial FibrillationAutomobile DrivingCCL2 geneCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCalcineurin inhibitorCalciumCalpainCaringCessation of lifeChest PainClinicalComplicationCongestive Heart FailureConnexin 43ConnexinsCytomegalovirusDataDependovirusDeveloped CountriesDevelopmentDilated CardiomyopathyDiseaseDominant-Negative MutationDyspneaEFRACEGF geneElementsEpidermal Growth FactorEyeFOSL2 geneFOXO1A geneFatigueFutureGene TransferGenesGeneticGuanosine Triphosphate PhosphohydrolasesHDAC4 geneHealth Care CostsHeartHeart AtriumHeart failureHospitalizationIndividualInterventionInvestigationLeft Ventricular Ejection FractionLeft atrial structureLeft ventricular structureLightheadednessMAP2K1 geneMAPK1 geneMAPK8 geneMethodsMinorMitogen-Activated Protein KinasesMitogensMolecularMutationMyocardiumNamesNodalOncogenesPalpitationsPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPharmacotherapyPhosphotransferasesPolymerase Chain ReactionPotassium ChannelPreclinical TestingProbabilityProceduresProtein KinaseProteinsPublic HealthRattusRecording of previous eventsRecurrenceRefractoryRegimenRibosomal Protein S6 KinaseRibosomesRiskRoleSignal PathwaySignal TransductionSinusStrokeSymptomsToxic effectTransforming Growth FactorsTransgenesTranslatingTranslationsVirionatrioventricular nodebasecalmodulin-dependent protein kinase IIclinically relevantconnexin 40effective therapyextracellularfibrosarcomagene therapygenetic inhibitorheart rhythmnovelnuclear factors of activated T-cellsosteosarcomap38 Mitogen Activated Protein Kinaseporcine modelpreventpromotersarcomaside effectstructural heart diseasesuccesstranscription 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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J Kevin Donahue其他文献
J Kevin Donahue的其他文献
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{{ truncateString('J Kevin Donahue', 18)}}的其他基金
Translating post-infarct ventricular tachycardia mechanisms into a therapy
将梗死后室性心动过速机制转化为治疗方法
- 批准号:
10608264 - 财政年份:2023
- 资助金额:
$ 83.01万 - 项目类别:
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:
10604289 - 财政年份:2021
- 资助金额:
$ 83.01万 - 项目类别:
A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation
AdKCNH2-G628S 基因治疗术后房颤的 I 期试验
- 批准号:
10513931 - 财政年份:2021
- 资助金额:
$ 83.01万 - 项目类别:
A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation
AdKCNH2-G628S 基因治疗术后房颤的 I 期试验
- 批准号:
10703247 - 财政年份:2021
- 资助金额:
$ 83.01万 - 项目类别:
A phase I trial of AdKCNH2-G628S gene therapy for post-op atrial fibrillation
AdKCNH2-G628S 基因治疗术后房颤的 I 期试验
- 批准号:
10276899 - 财政年份:2021
- 资助金额:
$ 83.01万 - 项目类别:
Final preclinical development of AAV gene therapy for atrial fibrillation
房颤 AAV 基因治疗的最终临床前开发
- 批准号:
9476321 - 财政年份:2016
- 资助金额:
$ 83.01万 - 项目类别:
Final preclinical development of AAV gene therapy for atrial fibrillation
房颤 AAV 基因治疗的最终临床前开发
- 批准号:
9288221 - 财政年份:2016
- 资助金额:
$ 83.01万 - 项目类别:
Transdisciplinary Training In Cardiovascular Research
心血管研究的跨学科培训
- 批准号:
10270065 - 财政年份:2014
- 资助金额:
$ 83.01万 - 项目类别:
Transdisciplinary Training In Cardiovascular Research
心血管研究的跨学科培训
- 批准号:
10671631 - 财政年份:2014
- 资助金额:
$ 83.01万 - 项目类别:
Preclinical gene therapy development for post-operative atrial fibrillation
术后房颤的临床前基因治疗开发
- 批准号:
8512334 - 财政年份:2013
- 资助金额:
$ 83.01万 - 项目类别:
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