Autonomic remodeling and modulation therapy in heart failure and sudden death

心力衰竭和猝死的自主神经重塑和调节治疗

基本信息

批准号：
9014077
负责人：
Deeptankar DeMazumder
金额：
$ 17.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014077
关键词：
Accounting Action Potentials Acute Adoption Adrenergic Agents Adrenergic Receptor American Antibodies Autonomic Dysfunction Behavior Biological Markers Canis familiaris Cardiac Cavia Cessation of life Chronic Clinical Data Development Diagnosis Disease Echocardiography Electrocardiogram Equilibrium Functional disorder Gene Proteins Goals Heart failure Human In Vitro Incidence Individual Industry Ion Channel Learning Left Left Ventricular Function Link Mechanics Mediating Medical Mentors Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinics Muscle Cells Pathway interactions Patients Phase Phenotype Physiologic pulse Play Process Property Proteins Proteome Proteomics Receptor Signaling Recovery Risk Role Signal Transduction Staging Sudden Death Techniques Testing Time Traction Training United States Vagus nerve structure Ventricular Work cardiac resynchronization therapy career clinical application clinically relevant effective therapy heart cell hemodynamics high risk implantation improved in vivo insight knock-down novel novel therapeutics programs protein function receptor-mediated signaling response restoration small hairpin RNA sudden cardiac death tool transcriptome transcriptomics translational medicine vagus nerve stimulation

项目摘要

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) claims a quarter millions lives per year in the United States. Individuals with heart failure (HF) are at a higher risk for SCD. The mechanistic link between HF and SCD has not been determined. The hallmark of HF and SCD is autonomic dysfunction. Whereas β-adrenergic (sympathetic) signaling has been extensively studied in HF, relatively little is known about the role of muscarinic (parasympathetic) signaling. Recent work by the PI has demonstrated that remodeling of muscarinic receptors is a critical component of the pathophysiology of HF. Further, cardiac resynchronization therapy (CRT), the only HF therapy to improve both acute and chronic cardiac function and survival differentially remodels muscarinic receptors to improve sympathovagal balance, β-adrenergic responsiveness, Ca+2 handling and contraction. Therapy with vagus nerve stimulation (VNS) has salutary effects in HF patients, similar to CRT. The underlying mechanisms are largely unknown. This proposal leverages a novel guinea pig model of hypertrophic heart failure that recapitulates many features of human HF, including prolonged QT interval and a high incidence of spontaneous arrhythmic SCD. Using this unique model, the PI's novel findings and VNS, a promising new HF therapy, this proposal will test the hypothesis that time-dependent changes in mAChR expression and signaling play a critical role in the development of HF/SCD and these can be reversed by chronic VNS. The specific aims will explore new fundamental mechanistic information about how and when in the disease process mAChR remodeling may be beneficial or pathological, while testing exciting new therapies for HF/SCD. We will identify key proteins, pathways and biomarkers modified by chronic VNS using differential transcriptomics and proteomics ("omics"). Changes in myocyte properties are manifested in transcriptome and proteome, contributing to the HF/SCD phenotype. Echocardiography, continuous ECG and in vivo hemodynamic studies will parallel the molecular/cellular studies. In ex vivo studies, antibodies and pharmacological agents will be used to test key signaling components. The proposed program is part of the PI's long term goal to investigate molecular mechanisms of cardiac function for the development of new exciting therapies for HF and SCD.

描述（由申请人提供）：在美国，每年有 25 万人死于心源性猝死（SCD）。心力衰竭（HF）患者发生 SCD 的风险较高。 HF 和 SCD 之间的机制尚未明确。 HF 和 SCD 的特点是自主神经功能障碍，而 β-肾上腺素能（交感神经）信号传导主要在 HF 中进行研究，但对于毒蕈碱的作用知之甚少。 PI 最近的工作表明，毒蕈碱受体的重塑是心力衰竭病理生理学的关键组成部分。此外，心脏再同步治疗 (CRT) 是唯一能够改善急性和慢性心脏功能和生存率的心力衰竭治疗方法。差异性地重塑毒蕈碱受体，以改善交感迷走神经平衡、β-肾上腺素能反应性、Ca+2 处理和收缩。与 CRT 类似，该方案利用了一种新型的肥厚性心力衰竭豚鼠模型，该模型概括了人类心力衰竭的许多特征，包括 QT 间期延长和自发性心律失常 SCD 的高发生率。利用这一独特的模型、PI 的新发现和 VNS（一种有前途的新型心力衰竭疗法），该提案将检验 mAChR 表达和信号传导的时间依赖性变化在发展中发挥关键作用的假设HF/SCD 的发生，这些可以通过慢性 VNS 来逆转，具体目标是探索新的基本机制信息，了解在疾病过程中 mAChR 重塑如何以及何时可能是有益的或病理性的，同时我们将测试令人兴奋的 HF/SCD 的新疗法。使用差异转录组学和蛋白质组学（“组学”）识别慢性 VNS 修饰的关键蛋白质、通路和生物标志物心肌细胞特性的变化体现在转录组和蛋白质组中，从而导致 HF/SCD。超声心动图、连续心电图和体内血流动力学研究将与分子/细胞研究并行，抗体和药物制剂将用于测试关键信号成分。心脏功能的分子机制，用于开发新的令人兴奋的 HF 和 SCD 疗法。