Altered CNS intercellular signaling mechanisms in cardiovascular disease

描述（由申请人提供）：神经体液激活，特征为交感神经张力升高、心血管反射减弱和激素血浆水平升高，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增加的神经体液驱动作为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抑制神经体液激活，因此未能改善这些心血管疾病的存活率或阻止其进展。虽然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起着重要作用，但这种改变背后的确切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），主要的前自主神经和神经内分泌脑中心之一，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，使用多学科的方法，范围从整个动物的单分子，我们建议使用PVN中央神经元回路和缺血性HF大鼠模型来测试一系列新的假设，旨在揭示基本的机械原理，涉及在健康和疾病条件下的心血管功能的中央控制。具体而言，我们提出了一个模型，其中PVN谷氨酸三分突触谷氨酸（GLU）突触输入，突触后交感PVN神经元，相关的星形胶质细胞，构成微调PVN神经元兴奋性和交感神经输出的关键结构/功能单位。我们推测，改变细胞间的通讯在这个单位有助于增强神经元的兴奋性和交感兴奋在HF。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-胶质细胞相互作用的变化有利于PVN三方功能单位内的兴奋性（直接兴奋性GLU作用）（目的1-3）而非抑制性（GLU介导的一氧化氮-GABA作用）（目的4）途径。提出的实验将确定潜在的前，后的ad突触外机制，有助于提高PVN神经元兴奋性和提高神经体液驱动在HF期间。此外，我们将测试一般的新假设，下丘脑星形胶质细胞有效地调节PVN神经元和突触功能，以及在健康和疾病条件下的交感兴奋驱动。总体而言，该项目将提供关键的和新的信息机制控制神经元兴奋性和细胞间通信的一个基本的前自主神经脑中心参与心血管功能的中央控制，并将揭示特定的病理生理机制的神经体液激活在心血管疾病。

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.