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

• 批准号: 10723916
• 负责人: Anna Pfenniger
• 金额: $ 16.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10723916
• 关键词: Age; Animal Model; Animals; Arrhythmia; Atrial Fibrillation; Award; Biology; Blood; Blood Vessels; Canis familiaris; Cardiac Myocytes; Cardiac ablation; Cardiovascular system; Chronic; Clinical; Coronary; Coupling; Data; Development; Diabetes Mellitus; Disease; Economic Burden; Electrophysiology (science); Endothelin A Receptor; Endothelin-1; Endothelium; Enzymes; Epidemic; Fatty acid glycerol esters; Fibrosis; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Generations; Genes; Genetic; Goals; Heart; Heart Atrium; Heart failure; Human; Hypertension; ITPR1 gene; Inflammatory; International; K-Series Research Career Programs; Kidney; Left; Left atrial structure; Lung; MLLT6 gene; Mentors; Mentorship; Microvascular Dysfunction; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Myocardium; National Heart, Lung, and Blood Institute; Nerve; Nerve Growth Factors; Pathway interactions; Patients; Peptides; Physicians; Prevalence; Profibrotic signal; Proteins; Public Health; Research; Research Institute; Risk Factors; Role; Scientist; Secondary to; Signal Pathway; Signal Transduction; Spatial Distribution; Strategic vision; Stroke; Testing; Time; United States National Institutes of Health; Universities; Ventricular; Work; autonomic nerve; canine model; cardiac magnetic resonance imaging; cardiovascular imaging; clinically relevant; endothelial dysfunction; gene therapy; heart rhythm; improved; interest; mortality; novel; novel therapeutics; pharmacologic; prevent; professor; programs; regional difference; skills; sleep health; small hairpin RNA; socioeconomics; spatial relationship; tool; translational potential

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.

摘要 心房颤动 (AF) 是最常见的持续性心律失常。它与重大的 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，因此这种心律失常是 成为一种流行病，带来严重的社会经济负担。不幸的是，目前 AF 的治疗方法是 次优：药物治疗和导管消融的疗效<50%，特别是在持续性 AF 中。一个 更好地了解房颤的分子机制对于开发新疗法至关重要。 AF 是一种多因素疾病，慢性损伤导致心肌进行性变化， 电气、结构和自主重塑。内皮功能障碍是大多数房颤危险因素的标志 包括心力衰竭、高血压和糖尿病。虽然多项研究表明两者之间存在关联 内皮功能障碍与 AF 之间的因果关系仍不清楚。 Pfenniger 博士提议进行调查 内皮功能障碍，特别是其主要效应物内皮素-1，在 AF 中的作用，使用两种临床方法 相关的 AF 大型动物模型，并利用具有高转化潜力的新型基因治疗工具。 该提案旨在首先表征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 的转变。此外，这项工作将旨在 确定 Endothelin-1 通过促进自主神经产生 AF 底物的机制， 心房的电和结构重塑。该提案的目标与 NHLBI 确定的目标紧密一致 战略眼光来研究新发现的对发病和发生重要的病理生物学机制 心、肺、血液和睡眠 (HLBS) 健康的进展。该职业发展奖将支持博士。 芬尼格向独立医师科学家的转变。 Pfenniger 博士目前是以下大学的助理教授 西北大学，获得 KL2 指导职业发展奖和 AHA 职业发展奖的支持 发展奖。 Pfenniger 博士将在范伯格心血管和肾脏研究所开展这项工作 西北大学研究所，主要导师为 Rishi Arora 博士。作为一名医学科学家 在电生理学领域，Pfenniger 博士将受益于 Arora 博士领导的指导团队的支持， 国际公认的医师科学家，专长于基础、转化和临床 电生理学，拥有 AF 大型动物模型方面的专业知识。导师的结合 独特的专业知识 – EC 耦合（Wasserstrom 博士）、高通量细胞电生理学（George 博士）、 血管生物学（Vaughan 博士）、转化性房颤研究（Passman 博士）、先进心血管成像 （Lee 博士和 Shah 博士）和心血管遗传学（Roy-Puckelwartz 博士）将使 Pfenniger 博士能够在她的基础上继续发展 现有的技能并帮助她在心律失常领域开拓自己的一片天地。临近年底 奖励期间，Pfenniger 博士将申请 NIH R01 奖励，利用该提案的结果开发一个 进一步研究内皮功能障碍在 AF 中的作用的独立研究计划。