Altered CNS Intercellular Signaling Mechanisms in Cardiovascular Disease

心血管疾病中中枢神经系统细胞间信号传导机制的改变

基本信息

批准号：
9084606
负责人：
Javier E Stern
金额：
$ 38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084606
关键词：
Affect Area Buffers Cardiovascular Diseases Cell Nucleus Coupling Data Development Disease Family Functional disorder Gene Expression Glutamates Health Heart failure Hormonal Hypothalamic structure Ion Channel Link Mediating Membrane Mitochondria Morbidity - disease rate N-Methyl-D-Aspartate Receptors N-Methylaspartate Neuraxis Neuronal Plasticity Neurons Neurosecretory Systems Neurotransmitters Nitric Oxide Organelles Patients Pattern Play Power Plants Production Property Public Health Rattus Receptor Activation Regulation Research Role Secondary to Series Shapes Signal Pathway Signal Transduction Source System TRP channel Testing Therapeutic Vasopressins Work density gamma-Aminobutyric Acid interdisciplinary approach mitochondrial dysfunction mitochondrial membrane mortality neuronal excitability novel receptor function spatiotemporal treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Neurohumoral activation, including sympathoexcitation and increased circulating hormonal levels such as vasopressin, is a major player in the pathophysiology of heart failure (HF), directly influencing morbidity and mortality i this disease. While the contribution of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei to neurohumoral activation in HF is established, a comprehensive understanding of the precise cellular mechanisms contributing to increased neuronal activity within these nuclei in HF remains elusive. Activity-dependent changes in neuronal intracellular Ca2+ levels (D[Ca2+]I)act as a critical signal influencing not only membrane excitability, but also neuroplasticity and gene expression. The excitatory transmitter glutamate, acting primarily via NMDA receptors (NMDAR), is a major source of D[Ca2+]I signaling (NMDA-DCa2+], playing an important role in the regulation of neurosecretory and presympathetic neuronal activity. Importantly, a growing body of evidence supports an exacerbated glutamate function in HF. Moreover, other signaling mechanisms that are directly linked to NMDA-DCa2+ (e.g, nitric oxide, ROS, GABA) are also altered in HF. The overall functional consequences of NMDA-DCa2+ are largely dependent on the spatiotemporal pattern of the D[Ca2+]I Thus, elucidating the precise mechanisms that influence the NMDA-DCa2+ properties, and how abnormal changes in these mechanisms may contribute to exacerbated neuronal activity in HF, is highly relevant. We have obtained exciting preliminary data supporting that mitochondria, classically viewed as static cellular power plants, are critical and dynamic organelles that actively influence NMDAR efficacy, by restraining its Ca2+-dependent coupling to other intracellular signaling pathways, influencing in turn overall SON/PVN neurosecretory and presympathetic neuronal activity. Moreover, we found that a blunted NMDAR- mitochondria crosstalk results in an enhanced NMDAR efficacy and exacerbated NMDA-DCa2+ leading to increased activation of the Ca2+- dependent family of TRP channels, and ultimately, abnormally elevated neuronal activity in HF. Here, we will test the central hypothesis that disruption of mitochondrial structurl-functional integrity results in exacerbated glutamate excitatory function, which via a strengthened coupling to Ca2+-sensitive TRPM4 channels, leads to enhanced neuronal activity in HF. This hypothesis will be tested in 3 specific aims: 1- To elucidate the role of mitochondria in shaping NMDAR-[Ca2+]i signaling in SON/PVN neurons, 2- To elucidate structural and functional mitochondrial mechanisms contributing to altered NMDAR-[Ca2+]i signaling in SON/PVN neurons HF rats, and 3- To determine the consequences of mitochondrial dysfunction on NMDAR-mediated neuronal excitability in HF rats. We expect results from this work to broaden our understanding of basic cellular mechanisms contributing to the hypothalamic regulation of neurohumoral outflows, and how changes in these mechanisms may contribute to neurohumoral activation in heart failure.

描述（由申请人提供）：神经肿瘤激活，包括交感神经和循环激素水平，例如加压素，是心力衰竭病理生理学（HF）的主要参与者，直接影响了这种疾病的发病率和死亡率。尽管建立了下丘脑旁植物（PVN）和上核（SON）核对HF中神经肿瘤活化的贡献，但对有助于增加HF中这些核中神经元活性的精确细胞机制的精确细胞机制的全面了解仍然难以捉摸。神经元内Ca2+水平（D [Ca2+] i）的活性依赖性变化是影响膜兴奋性的关键信号，而且还影响神经可塑性和基因表达。主要通过NMDA受体（NMDAR）起作用的兴奋性发射机谷氨酸是D [Ca2+] I信号传导（NMDA-DCA2+]）的主要来源，在调节神经分泌术中起着重要作用。与NMDA-DCA2+（例如，一氧化氮，ROS，GABA）的联系也改变了NMDA-DCA2+的总体功能后果，在很大程度上取决于D [CA2+]的时空模式[Ca2+] i，因此阐明了nmda-da-da-dap+ properties的贡献机制。加剧了HF的神经元活性，我们获得了令人兴奋的初步数据，该数据支持线粒体，通常被视为静态细胞发电厂，是关键的和动态的细胞器 NMDAR功效通过将其Ca2+依赖性耦合限制在其他细胞内信号通路上，从而影响整个SON/PVN神经分泌和相关神经元活性。此外，我们发现钝的NMDAR-线粒体串扰会导致NMDAR功效增强并加剧了NMDA-DCA2+的加剧，从而导致Ca2+依赖性的TRP通道的激活增加，最终使HF中的神经元活性异常升高。在这里，我们将测试中心假设，即线粒体结构功能完整性的破坏会导致谷氨酸兴奋性功能加剧，这通过加强与Ca2+敏感的TRPM4通道的耦合导致HF中的神经元活性增强。该假设将以3个特定目的进行检验：1-阐明线粒体在SON/PVN神经元中塑造NMDAR- [Ca2+] I信号传导中的作用，2-阐明了结构性和功能性的线粒体机制，从而改变了NMDAR- [CA2+] IN NEURONS IN-SON/PVN-y-pvn NEURONS的作用，r- HF大鼠NMDAR介导的神经元兴奋性的线粒体功能障碍。我们期望这项工作的结果扩大我们对有助于下丘脑神经肿瘤流出的下丘脑调节的基本细胞机制的理解，以及这些机制的变化如何导致心力衰竭的神经肿瘤激活。