Role of Endothelin-1 signaling in the development and progression of atrial fibrillation
Endothelin-1 信号传导在心房颤动发生和进展中的作用
基本信息
- 批准号:10723916
- 负责人:
- 金额:$ 16.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAnimal ModelAnimalsArrhythmiaAtrial FibrillationAwardBiologyBloodBlood VesselsCanis familiarisCardiac MyocytesCardiac ablationCardiovascular systemChronicClinicalCoronaryCouplingDataDevelopmentDiabetes MellitusDiseaseEconomic BurdenElectrophysiology (science)Endothelin A ReceptorEndothelin-1EndotheliumEnzymesEpidemicFatty acid glycerol estersFibrosisFutureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGene ExpressionGenerationsGenesGeneticGoalsHeartHeart AtriumHeart failureHumanHypertensionITPR1 geneInflammatoryInternationalK-Series Research Career ProgramsKidneyLeftLeft atrial structureLungMLLT6 geneMentorsMentorshipMicrovascular DysfunctionModelingMolecularMorbidity - disease rateMuscle CellsMyocardiumNational Heart, Lung, and Blood InstituteNerveNerve Growth FactorsPathway interactionsPatientsPeptidesPhysiciansPrevalenceProfibrotic signalProteinsPublic HealthResearchResearch InstituteRisk FactorsRoleScientistSecondary toSignal PathwaySignal TransductionSpatial DistributionStrategic visionStrokeTestingTimeUnited States National Institutes of HealthUniversitiesVentricularWorkautonomic nervecanine modelcardiac magnetic resonance imagingcardiovascular imagingclinically relevantendothelial dysfunctiongene therapyheart rhythmimprovedinterestmortalitynovelnovel therapeuticspharmacologicpreventprofessorprogramsregional differenceskillssleep healthsmall hairpin RNAsocioeconomicsspatial relationshiptooltranslational potential
项目摘要
SUMMARY Atrial fibrillation (AF) is the most common sustained arrhythmia. It is associated with significant
morbidity and mortality, being a leading cause of stroke. As age is a major risk factor for AF, this arrhythmia is
becoming an epidemic, with significant socioeconomic burden. Unfortunately, current therapies for AF are
suboptimal: pharmacologic therapies and catheter ablation have <50% efficacy, particularly in persistent AF. A
better understanding of the molecular mechanisms of AF will be crucial for the development of new therapies.
AF is a multifactorial disease, with chronic insults leading to progressive changes in the myocardium with
electrical, structural and autonomic remodeling. Endothelial dysfunction is a hallmark of most risk factors for AF
including heart failure, hypertension and diabetes. While multiple studies showed an association between
endothelial dysfunction and AF, the causal relationship remains unknown. Dr Pfenniger proposes to investigate
the role of endothelial dysfunction, and specifically of its major effector Endothelin-1, in AF using two clinically
relevant large animal models of AF, and harnessing novel gene therapy tools with high translational potential.
This proposal aims to first characterize the temporal and spatial relationship between endothelial dysfunction
and AF, with a particular focus on the transition from paroxysmal to persistent AF. In addition, this work will aim
to determine the mechanisms by which Endothelin-1 creates an AF substrate by promoting autonomic,
electrical and structural atrial remodeling. The objective of this proposal aligns closely with NHLBI's identified
strategic vision to investigate newly discovered pathobiological mechanisms important to the onset and
progression of heart, lung, blood, and sleep (HLBS) health. This Career Development Award will support Dr.
Pfenniger's transition to an independent physician-scientist. Dr. Pfenniger is currently an Assistant Professor at
Northwestern University, with the support of a KL2 Mentored Career Development Award and an AHA Career
Development Award. Dr. Pfenniger will carry out this work at the Feinberg Cardiovascular and Renal Research
Institute at Northwestern University under the primary mentorship of Dr. Rishi Arora. As a physician-scientist in
electrophysiology, Dr. Pfenniger will uniquely benefit from the support of her mentoring team led by Dr. Arora,
an internationally recognized physician-scientist with specialization in basic, translational and clinical
electrophysiology, who possesses expertise in large animal models of AF. The combination of mentors with
distinct expertise – EC coupling (Dr. Wasserstrom), high-throughput cellular electrophysiology (Dr. George),
vascular biology (Dr. Vaughan), translational AF research (Dr. Passman), advanced cardiovascular imaging
(Drs. Lee and Shah), and cardiovascular genetics (Dr. Roy-Puckelwartz) will allow Dr. Pfenniger to build on her
current skills and help her carve out her own niche in the field of heart rhythm disorders. Near the end of the
award period, Dr. Pfenniger will apply for a NIH R01 award, using the results of this proposal to develop an
independent research program to further study the role of endothelial dysfunction in AF.
心房颤动(AF)是最常见的持续性心律失常。它与重要的
发病率和死亡率,是中风的主要原因。由于年龄是房颤的主要危险因素,
成为一种流行病,带来巨大的社会经济负担。不幸的是,目前的AF治疗方法
次优:药物治疗和导管消融的有效性<50%,特别是在持续性房颤中。
更好地了解房颤的分子机制对于开发新的治疗方法至关重要。
AF是一种多因素疾病,慢性损伤导致心肌进行性变化,
电重构、结构重构和自主重构。内皮功能障碍是房颤的主要危险因素
包括心力衰竭高血压和糖尿病虽然多项研究表明,
内皮功能障碍和房颤,因果关系仍未知。普芬尼格博士打算研究
内皮功能障碍,特别是其主要效应因子内皮素-1在房颤中的作用,
AF的相关大型动物模型,并利用具有高翻译潜力的新型基因治疗工具。
该建议旨在首先描述内皮功能障碍之间的时间和空间关系
和AF,特别关注从阵发性AF到持续性AF的过渡。此外,这项工作将旨在
为了确定内皮素-1通过促进自主神经产生AF底物的机制,
心房电重构和结构重构。本提案的目标与NHLBI确定的
研究新发现的对发病重要的病理生物学机制的战略眼光,
心脏、肺、血液和睡眠(HLBS)健康的进展。这个职业发展奖将支持博士。
Pfenniger的过渡到一个独立的物理学家,科学家。Pfenniger博士目前是助理教授,
西北大学,在KL 2指导职业发展奖和AHA职业发展奖的支持下
发展奖。Pfenniger博士将在Feinberg心血管和肾脏研究中心开展这项工作
在西北大学的Rishi Arora博士的主要指导下研究所。作为一名物理学家,
电生理学,Pfenniger博士将独特地受益于由Arora博士领导的指导团队的支持,
国际公认的医生,科学家与基础,转化和临床专业化
电生理学,谁拥有专业知识,在大型动物模型的AF。
独特的专业知识- EC偶联(Wasserstrom博士),高通量细胞电生理学(乔治博士),
血管生物学(Vaughan博士)、转化性房颤研究(Passman博士)、高级心血管成像
(Drs. Lee和Shah)和心血管遗传学(Roy-Puckelwartz博士)将允许Pfenniger博士在她的基础上进行研究。
目前的技能,并帮助她开拓自己的利基领域的心脏节律紊乱。接近尾声
在奖励期间,Pfenniger博士将申请NIH R 01奖,使用该提案的结果来开发一个
独立研究项目,以进一步研究内皮功能障碍在AF中的作用。
项目成果
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