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: 8011516
• 负责人: Javier E Stern
• 金额: $ 36.79万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011516
• 关键词: Address; Animals; Astrocytes; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chronic; Cleaved cell; Communication; Complex; Consensus; Disease; Equilibrium; Excitatory Amino Acids; Functional disorder; Glutamate Receptor; Glutamates; Goals; Health; Heart failure; Hormonal; Hypertension; Hypothalamic structure; Kidney; Laboratories; Lead; Mediating; Modeling; Molecular Conformation; Myocardial Ischemia; NR1 gene; Names; Nature; Nerve; Neurons; Neurosecretory Systems; Neurotransmitters; Nitric Oxide; Output; Pathway interactions; Patients; Plasma; Play; Principal Investigator; Probability; Production; Protein Isoforms; Public Health; Rattus; Reflex action; Research; Research Personnel; Risk; Role; Secondary to; Series; Signal Transduction; Source; Synapses; Synaptic Cleft; System; Techniques; Testing; Therapeutic; Work; density; gamma-Aminobutyric Acid; improved; innovation; intercellular communication; interdisciplinary approach; mortality; multidisciplinary; neuronal circuitry; neuronal excitability; novel; outcome forecast; paraventricular nucleus; postsynaptic; presynaptic; prevent; programs; receptor; research study; single molecule; synaptic function

DESCRIPTION (provided by applicant): Neurohumoral activation, characterized by elevated sympathetic tone, blunted cardiovascular reflexes, and elevated hormonal plasma levels, is a common finding in a variety of cardiovascular diseases, including hypertension and heart failure (HF). Despite compelling evidence supporting increased neurohumoral drive as a major determinant of patients' prognosis and mortality, none of the current therapeutic strategies efficiently inhibit neurohumoral activation, failing thus to improve the survival or stop the progression of these cardiovascular diseases. Although altered central autonomic function plays an important role in the pathophysiology of major cardiovascular diseases, the precise cellular mechanisms underlying such alteration are still poorly understood. Recent studies from our laboratories indicate that neuronal activation within the hypothalamic paraventricular nucleus (PVN), one of the major preautonomic and neuroendocrine brain centers, contributes to elevated neurohumoral drive in cardiovascular disease states. Here, using a multidisciplinary approach that ranges from the whole animal to single molecules, we propose to use the PVN central neuronal circuitry and a rat model of ischemic HF to test a series of novel hypotheses that aim to unveil basic mechanistic principles involved in the central control of cardiovascular function in health and disease conditions. Specifically, we propose a model in which PVN glutamate tripartite synapses represented by glutamate (GLU) synaptic inputs, postsynaptic sympathetic PVN neurons, and associated astrocytes, constitute key structural/functional units fine-tuning PVN neuronal excitability and sympathetic output. We hypothesize that altered intercellular communication within this unit contributes to enhanced neuronal excitability and sympathoexcitation during HF. We propose that during HF, structural/functional reconfiguration of GLU afferent inputs, changes in GLU receptor portfolios, and changes in neuronal-glial interactions favors excitatory (direct excitatory GLU action) (Aims 1-3) over inhibitory (GLU-mediated nitric oxide-GABA action) (Aim 4) pathways within the PVN tripartite functional unit. The proposed experiments will identify the underlying pre-, post- ad extrasynaptic mechanisms contributing to elevated PVN neuronal excitability and elevated neurohumoral drive during HF. In addition, we will test the general novel hypothesis that hypothalamic astrocytes efficiently modulate PVN neuronal and synaptic function, as well as sympathoexcitatory drive in health and disease conditions. Overall, this project will provide critical and novel information on mechanisms controlling neuronal excitability and intercellular communication within a fundamental preautonomic brain center involved in the central control of cardiovascular function, and will unveil specific pathophysiological mechanisms underlying neurohumoral activation in cardiovascular diseases.

描述（由申请人提供）：以交感神经张力升高、心血管反射减弱和血浆激素水平升高为特征的神经体液激活是多种心血管疾病（包括高血压和心力衰竭（HF））的常见发现。尽管有令人信服的证据支持神经体液驱动的增加是患者预后和死亡率的主要决定因素，但目前的治疗策略都没有有效地抑制神经体液激活，从而未能提高这些心血管疾病的生存率或阻止其进展。尽管中枢自主神经功能的改变在主要心血管疾病的病理生理学中发挥着重要作用，但这种改变背后的精确细胞机制仍然知之甚少。我们实验室的最新研究表明，下丘脑室旁核（PVN）（主要的自主神经前和神经内分泌大脑中心之一）内的神经元激活有助于心血管疾病状态下神经体液驱动的提高。在这里，我们使用从整个动物到单个分子的多学科方法，建议使用 PVN 中枢神经元回路和缺血性心力衰竭大鼠模型来测试一系列新颖的假设，旨在揭示中枢神经元回路中涉及的基本机制原理。在健康和疾病条件下控制心血管功能。具体来说，我们提出了一个模型，其中由谷氨酸（GLU）突触输入、突触后交感PVN神经元和相关星形胶质细胞代表的PVN谷氨酸三联突触构成微调PVN神经元兴奋性和交感神经输出的关键结构/功能单元。我们假设该单元内细胞间通讯的改变有助于增强心力衰竭期间的神经元兴奋性和交感神经兴奋。我们提出，在 HF 期间，GLU 传入输入的结构/功能重新配置、GLU 受体组合的变化以及神经元-胶质细胞相互作用的变化有利于兴奋性（直接兴奋性 GLU 作用）（目标 1-3）而不是抑制性（GLU 介导的一氧化氮） -GABA 作用）（目标 4）PVN 三方功能单元内的途径。拟议的实验将确定导致 HF 期间 PVN 神经元兴奋性升高和神经体液驱动升高的潜在前、后突触外机制。此外，我们将测试一般性的新假设，即下丘脑星形胶质细胞有效调节 PVN 神经元和突触功能，以及健康和疾病条件下的交感神经兴奋驱动。总体而言，该项目将提供有关控制心血管功能中枢控制的基本前自主脑中心内神经元兴奋性和细胞间通讯的机制的关键和新颖的信息，并将揭示心血管疾病中神经体液激活的具体病理生理机制。