Peptidergic modulation of guinea pig intrinsic cardiac neurons

豚鼠内在心脏神经元的肽能调节

• 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
• 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

 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.

 描述(申请人提供)：慢性心脏病导致心脏组织和控制心脏的神经系统内的功能和表型变化。自主神经控制失衡，导致副交感神经活动减少，加上交感神经活动增加和异质性，增加了心律失常和猝死的风险。心脏固有神经系统(ICN)是副交感神经自主控制心脏的最终共同途径，它集成了来自多个输入的信息，可以在每跳的基础上产生对心脏功能的短环反射控制。虽然许多研究都集中在心脏应激引起的交感神经元控制的变化上，但对外周副交感自主神经节内信息处理的关键作用以及它们如何重塑/适应施加的应激的关注要少得多。我们的假设是，心脏应激诱导的心脏固有神经系统内的适应代表了通过选择心脏固有神经元群体的功能和表型变化来维持副交感传出输出的努力。ICN内的这些适应可以部分抵消与进行性心脏病相关的过度和异质性交感兴奋的不适应效应。交感神经传出活性的增加可通过交感神经传出纤维释放去甲肾上腺素和神经肽Y(NPY)，以及交感神经诱导的多肽激素血管紧张素II(AngII)及其代谢物Ang(1-7)的产生增加来改变心功能。为了明确说明多肽水平改变在心脏病理发展中的重要性，这项建议将评估豚鼠心肌梗死(MI)后心脏固有神经系统对AngII和NPY水平升高的反应。利用豚鼠心神经丛的整体制备，我们将评估单个心脏固有神经元对对照组和心肌梗塞动物组织中血管紧张素Ⅱ和神经肽Y的生理反应。我们的主要目标是(1)确定血管紧张素II受体(AT1R、AT2R、MASR)在心肌梗死后ICN输出调节中的作用；(2)确定心肌梗死后NPY释放增加对ICN的影响。我们将使用一种多学科的方法，其中包括在整个安装准备过程中单个神经元的尖锐电极电压记录，完整网络中神经元的整个细胞电压钳记录，免疫组织化学，以及蛋白质和mRNA表达水平的生化测量。综合起来，这些研究的结果将有助于确定这些多肽调节神经功能的机制。这些信息可以用来开发治疗慢性心脏病的更好的药物疗法。