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：
9405941
负责人：
Deeptankar DeMazumder
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405941
关键词：
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 Hyperactive behavior In Vitro Incidence Individual Industry Ion Channel Learning Left Left Ventricular Function Link Mechanics Mediating Medical Mentors Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinic M2 Receptor Muscarinic M3 Receptor Muscarinics Muscle Cells Pathologic Pathway interactions Patients Pharmacology Phase Phenotype Physiologic pulse Play Process Property Proteins Proteome Proteomics Receptor Signaling Recovery Risk Role Signal Transduction Sudden Death Techniques Testing Time Traction Training Treatment Failure United States Vagus nerve structure Ventricular Work cardiac resynchronization therapy cardiogenesis career clinical application clinically relevant effective therapy gene function heart cell hemodynamics high risk implantation improved in vivo insight knock-down novel novel therapeutics programs protein function receptor expression 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）：突然的心脏死亡（SCD）索赔人佩雷斯人（HF）尚未确定HF和SCD之间的机械链接。 SCD是自主的功能障碍。功能和生存差异化毒蕈碱受体以改善交感神经的疾病，CA+2处理和收缩的效果。人类HF，间隔和自发性心律失常SCD的许多特征。在疾病过程中如何以及何时进行MACHR重塑可能是有益的，病理或病理的，同时测试了HF/SCD的令人兴奋的新疗法，我们将使用多种粘液量和蛋白质组学变化来识别慢性VN修饰的关键蛋白质，途径和生物标志物特性在转录组和蛋白质组中，有助于HF/SCD表型。 - 从IAC功能开发新的令人兴奋的Forf和SCD的刺激性疗法的对象分子机制。