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.

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）将使Pfenniger博士能够在她的基础上继续发展 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。