Altered CNS intercellular signaling mechanisms in cardiovascular disease

描述（由申请人提供）：神经体液激活，以交感神经张力升高、心血管反射迟钝和激素血浆水平升高为特征，是包括高血压和心力衰竭（HF）在内的多种心血管疾病的常见发现。尽管有令人信服的证据支持神经体液驱动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，因此未能提高生存率或阻止这些心血管疾病的进展。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中起着重要作用，但这种改变背后的精确细胞机制仍然知之甚少。我们实验室最近的研究表明，下丘脑室旁核（PVN）是主要的自主神经和神经内分泌脑中心之一，其神经元激活有助于心血管疾病状态下神经体液驱动的升高。在这里，我们采用多学科方法，从整个动物到单分子，我们建议使用PVN中枢神经回路和缺血性HF大鼠模型来测试一系列新的假设，旨在揭示在健康和疾病条件下参与心血管功能中枢控制的基本机制原理。具体来说，我们提出了一个模型，在该模型中，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谷氨酸三方突触构成了调节PVN神经元兴奋性和交感输出的关键结构/功能单位。我们假设，在心衰期间，细胞间通讯的改变有助于增强神经元的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/功能重构、GLU受体组合的变化以及神经元-胶质相互作用的变化有利于PVN三方功能单元中的兴奋性（直接兴奋性GLU作用）途径（Aims 1-3）而非抑制性（GLU介导的一氧化氮- gaba作用）途径（Aim 4）。提出的实验将确定心衰期间PVN神经元兴奋性升高和神经体液驱动升高的潜在前、后和突触外机制。此外，我们将验证下丘脑星形胶质细胞在健康和疾病条件下有效调节PVN神经元和突触功能以及交感兴奋驱动的一般新假设。总的来说，该项目将提供重要的和新颖的信息，以控制神经兴奋性和细胞间通讯的机制，在一个基本的前自主脑中心参与心血管功能的中央控制，并将揭示心血管疾病中神经体液激活的特定病理生理机制。

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.