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Peptidergic modulation of guinea pig intrinsic cardiac neurons

豚鼠内在心脏神经元的肽能调节

基本信息

批准号：
9097937
负责人：
JEAN C HARDWICK
金额：
$ 36.58万
依托单位：
ITHACA COLLEGE
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：
2016-04-05 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097937
关键词：
AGTR2 gene Acute Address Adrenergic Agents Adrenergic Fibers Angiotensin II Angiotensin II Receptor Animal Model Animals Arrhythmia Attention Autonomic ganglion Autonomic nervous system Biochemical Cardiac Cardiac development Cavia Cells Chronic Cleaved cell Coupled Electrodes Fiber Heart Heart Diseases Immunohistochemistry Individual Lead Measurement Mediating Myocardial Infarction Nervous system structure Neurons Neuropeptide Y Receptor Neuropeptides Norepinephrine Output Pathology Pathway interactions Pattern Peptides Peripheral Pharmacotherapy Physiological Population Preparation Production Reflex control Research Risk Role Signal Transduction Signaling Molecule Stress Structure of parasympathetic ganglion Sudden Death System Techniques Time Tissues Western Blotting base expectation fiber cell information processing interdisciplinary approach mRNA Expression neuropeptide Y neuroregulation outcome forecast peptide hormone postsynaptic presynaptic protein expression public health relevance receptor receptor expression response targeted treatment voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Chronic heart disease induces functional and phenotypic changes within cardiac tissues and the neuronal systems that control the heart. An imbalance in autonomic neuronal control that results in reduced parasympathetic activity coupled with increased and heterogeneous sympathetic activity increases the risk of cardiac arrhythmias and sudden death. The intrinsic cardiac nervous system (ICN), the final common pathway for parasympathetic autonomic control to the heart, integrates information from multiple inputs and can produce short-loop reflex control of cardiac function on a beat-to-beat basis. While multiple studies have focused on cardiac stress-induced changes in sympathetic neuronal control, much less attention has been paid to the critical role of information processing within peripheral parasympathetic autonomic ganglia and how they remodel/adapt to imposed stress. It is our hypothesis that cardiac stress-induced adaptations within the intrinsic cardiac nervous system represent efforts to maintain parasympathetic efferent output via functional and phenotypic alterations in select intrinsic cardiac neuronal populations. These adaptations within the ICN could counteract, in part, the maladaptive effects of excessive and heterogeneous sympathetic excitation associated with progressive cardiac disease. Increased sympathetic efferent activity can alter cardiac function through increased release of norepinephrine and neuropeptide Y (NPY) from sympathetic efferent fibers, along with sympathetic-induced increases in the production of the peptide hormone angiotensin II (AngII) and its metabolite, Ang(1-7). To specifically address the importance of altered peptide levels on the development of cardiac pathology, this proposal will evaluate how the intrinsic cardiac nervous system responds to elevated levels of AngII and NPY following myocardial infarction (MI) in the guinea pig. Using a whole mount preparation of the guinea pig cardiac plexus, we will evaluate the physiological responses of individual intrinsic cardiac neurons to AngII and NPY in tissues from control and MI animals. Our primary specific aims are (1) to determine the role of Angiotensin II receptors (AT1R, AT2R, MasR) in the modulation of ICN output with MI and (2) to determine the effects of increased release of NPY on the ICN following MI. We will use a multidisciplinary approach, which includes sharp electrode voltage recordings from individual neurons in the whole mount preparation, whole cell voltage clamp recordings from neurons within the intact network, immunohistochemistry, and biochemical measurements of protein and mRNA expression levels. Combined, the results from these studies will aid in determining the mechanisms by which these peptides can modulate neuronal function. This information can be used to develop better pharmacotherapies to treat chronic heart disease.