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

• 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
• 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

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（由申请方提供）：神经体液激活，包括交感神经兴奋和循环激素水平升高（如加压素），是心力衰竭（HF）病理生理学的主要参与者，直接影响该疾病的发病率和死亡率。虽然下丘脑室旁核（PVN）和视上核（SON）对HF中神经体液激活的贡献已经建立，但对HF中这些核团内神经元活动增加的精确细胞机制的全面理解仍然是难以捉摸的。神经元内Ca 2+水平（D[Ca 2 +]I）的活动依赖性变化不仅作为影响膜兴奋性的关键信号，而且作为影响神经可塑性和基因表达的关键信号。兴奋性递质谷氨酸主要通过NMDA受体（NMDAR）起作用，是D[Ca 2 +]I信号（NMDA-DCa 2+）的主要来源，在神经分泌和前交感神经元活动的调节中起重要作用。重要的是，越来越多的证据支持HF中谷氨酸功能的加剧。此外，与NMDA-DCa 2+直接相关的其他信号传导机制（例如，一氧化氮、ROS、GABA）也在HF中改变。NMDA-DCa 2+的整体功能结果在很大程度上取决于D[Ca 2 +]I的时空模式。因此，阐明影响NMDA-DCa 2+性质的精确机制以及这些机制中的异常变化如何导致HF中神经元活动加剧是高度相关的。我们已经获得了令人兴奋的初步数据，支持线粒体，传统上被视为静态细胞发电厂，是积极影响的关键和动态细胞器， NMDAR功效，通过抑制其与其他细胞内信号传导途径的Ca 2+依赖性偶联，进而影响总体SON/PVN神经分泌和前交感神经元活性。此外，我们发现钝化的NMDAR-线粒体串扰导致NMDAR功效增强并加剧NMDA-DCa 2+，导致TRP通道的Ca 2+依赖性家族的活化增加，并最终导致HF中神经元活性异常升高。在这里，我们将测试的核心假设，即线粒体结构功能的完整性的破坏导致谷氨酸兴奋性功能加剧，这通过加强耦合到Ca 2 +-敏感的TRPM 4通道，导致增强的神经元活动在HF。该假设将在3个具体目标中进行测试：1-阐明线粒体在形成SON/PVN神经元中的NMDAR-[Ca 2 +]i信号传导中的作用，2-阐明有助于改变SON/PVN神经元HF大鼠中的NMDAR-[Ca 2 +]i信号传导的结构和功能线粒体机制，以及3-确定线粒体功能障碍对HF大鼠中NMDAR介导的神经元兴奋性的后果。我们期望这项工作的结果，以扩大我们的理解，有助于下丘脑调节神经体液流出的基本细胞机制，以及如何在这些机制的变化可能有助于心力衰竭的神经体液激活。