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Peripheral Sympathetic Dysfunction in Cardiac Disease

心脏病中的周围交感功能障碍

基本信息

批准号：
10133133
负责人：
BETH A HABECKER
金额：
$ 76.83万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133133
关键词：
3-Dimensional Address Animal Model Arrhythmia Brown Fat Calcium Calcium Signaling Cardiac Cardiovascular Diseases Cardiovascular Pathology Cause of Death Cells Coupled Data Dendrites Development Devices Disease Electrophysiology (science)Fostering Functional disorder Future Ganglia Genetic Goals Heart Heart Diseases Heart failure Hyperactivity Intervention Ischemia Label Life Link Measures Modeling Morphology Mus Myocardial Infarction Nervous system structure Neuraxis Neuronal Plasticity Neurons Neurophysiology - biologic function Norepinephrine Pathologic Pathology Patients Peripheral Preparation Process Reperfusion Therapy Research Research Design Risk Role Signal Transduction Structure Structure of stellate ganglion Sympathetic Nervous System Synapses Testing Therapeutic Therapeutic Intervention Tracer Transgenic Mice United States Ventricular Arrhythmia Work base cholinergic constriction experimental study high risk insight mouse genetics mouse model neurochemistry neuronal excitability neuropeptide Y neuroregulation new therapeutic target novel novel therapeutics patch clamp prevent reconstruction single-cell RNA sequencing sudden cardiac death targeted treatment tool translational study transmission process voltage

项目摘要

Project Summary Myocardial infarction and heart failure increase risk for ventricular arrhythmias and sudden cardiac death. Autonomic dysregulation and sympathetic hyperactivity accompany these diseases and trigger lethal arrhythmias. Interventions that target the central nervous system to inhibit sympathetic outflow have not been effective in patients, but interventions that target the peripheral sympathetic nervous system decrease arrhythmias and prolong life. We hypothesize that central nervous system activity is amplified by post- ganglionic neurons in cardiovascular disease to enhance norepinephrine and neuropeptide Y release at the heart, which contributes to pathology. We have discovered excitatory collaterals between sympathetic post- ganglionic neurons that foster synchronous amplification of preganglionic signals. We hypothesize that disease-induced changes in the heart trigger morphological and electrical transformation of sympathetic postganglionic neurons that results in sympathetic hyperactivity. To identify the mechanisms responsible for hyper-sympathetic changes, we exploit transgenic mouse models coupled with neurochemistry, single cell RNAseq, patch clamp electrophysiology, retrograde tracing and 3D reconstruction of labeled neurons to link structure with function. We will connect neural function to norepinephrine and neuropeptide Y release in the heart. The combined power of single cell synaptic measures with mouse genetics and retrograde tracing offers unique opportunities to resolve mechanisms responsible for augmented transmission specific to cardiac projecting neurons. We will test the hypotheses that myocardial infarction and heart failure drive increased cardiac sympathetic transmission: through expanding dendritic arbors and their synaptic inputs (Aim 1); through enhancing neuronal activity (Aim 2); and through altering neuronal calcium handling (Aim 3). We have assembled a unique team of accomplished experts, key animal models, and powerful genetic tools to accomplish these studies. We expect that novel insights and targets for therapeutic intervention will come from the studies described here, and that this work with have implications for treatment of the many diseases characterized by high sympathetic activation.

项目总结