Central neuronal-glial mechanisms and neurohumoral activation in hypertension

描述(由申请人提供)：虽然交感神经和神经内分泌系统的协调活动对于适当维持心血管(CV)内环境平衡是必不可少的，但持续的交感神经体液激活是非常有害的，会导致包括高血压在内的心血管疾病。因此，阐明交感体液激活的调节机制对于高血压的预防和更有效的治疗至关重要。下丘脑室旁核(PVN)在交感体液反应的产生中起着关键作用。这个核团内的神经元活动受内在属性和外在突触输入之间的平衡控制。在最近的研究中，我们发现A-型钾电流(IA)抑制了PVN的放电活动，而IA功能的减弱有助于高血压时神经元活动的增强。高血压的另一个主要致病因素是谷氨酸NMDA受体功能增强。然而，这两种不同的机制是否在功能上和因果上耦合，目前尚不清楚。采用体外和体内研究相结合的多学科方法，我们获得了令人兴奋的初步数据，支持突触外NMDARs和IA之间存在因果联系，介导高血压患者神经元活性增加和交感神经激活。此外，我们发现星形胶质细胞是影响eNMDAR-IA偶联疗效的关键角色。在这项提案中，我们将检验这一中心假设，即eNMDAR的过度激活及其与IA的负耦合是导致高血压患者神经元活性增加和交感体液激活的主要因素。本应用程序的主要目标是表征eNMDAR-IA耦合背后的信号机制。此外，我们的目的是阐明(A)胶质功能改变和(B)内在神经机制在高血压大鼠eNMDAR-IA偶联过度激活、神经元活性增加和交感体液激活中的相对贡献。利用肾血管性高血压动物模型，我们提出了以下具体目标：目的1-表征eNMDAR和IA之间的功能偶联；目的2-确定胶质功能改变是否有助于高血压大鼠eNMDAR-IA偶联增强；以及目的3-确定神经元机制改变是否有助于高血压大鼠eNMDAR-IA偶联增强。我们期望这项工作能扩大我们对产生动态平衡神经体液反应所涉及的基本神经生物学原理的了解。更重要的是，我们希望确定导致高血压患者神经体液反应不良的关键病理生理脑机制。我们希望我们的工作将有助于开发新的、更有效的治疗高血压疾病的策略。 公共卫生相关性：高血压在美国是一个主要的公共卫生问题，其特征是自主神经和神经内分泌系统的活动增加(神经体液激活)，这对这些患者的发病率和死亡率有很大影响。然而，神经体液的确切机制仍不清楚。在这项提案中，我们将使用多学科方法来测试一系列新的假说，旨在阐明中枢神经系统内有助于高血压神经体液激活的信号机制。我们期望我们的工作为高血压患者神经功能改变的机制提供新的信息，并帮助开发新的、更有效的治疗高血压常见并发症的治疗策略。

DESCRIPTION (provided by applicant): While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of cardiovascular (CV) homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to CV disorders including hypertension. Thus, elucidating mechanisms regulating sympathohumoral activation is critical for the prevention and more efficient treatment of hypertension. The hypothalamic paraventricular (PVN) nucleus plays pivotal roles in the generation of sympathohumoral responses. Neuronal activity within this nucleus is controlled by a balance between intrinsic properties and extrinsic synaptic inputs. In recent studies, we showed that the A-type K+ current (IA) inhibits PVN firing activity, and that blunted IA function contributes to enhanced neuronal activity in hypertension. Another major pathogenic factor in hypertension is increased glutamate NMDA receptor function. However, whether these two distinct mechanisms are functionally and causally coupled, is at present unknown. Using a multidisciplinary approach combining in vitro and in vivo studies, we obtained exciting preliminary data supporting a causal link between extrasynaptic NMDARs and IA in mediating increased neuronal activity and sympathoumoral activation in hypertension. Moreover we found astrocytes to be pivotal players influencing the efficacy of the eNMDAR-IA coupling. In this proposal, we will test the central hypothesis that over-activation of eNMDARs and its negative coupling to IA is a major contributing factor underlying increased neuronal activity and sympathohumoral activation in hypertension. The main objective of this application is to characterize the signaling mechanisms underlying the eNMDAR-IA coupling. Moreover, we aim to elucidate the relative contribution of (a) altered glial function and (b) intrinsic neuronal mechanisms to overactivation of the eNMDAR-IA coupling, and increased neuronal activity and sympathohumoral activation in hypertensive rats. Using a renovascular hypertensive animal model, we propose the following Specific Aims: Aim 1- To characterize the functional coupling between eNMDARs and IA; Aim 2- To determine if altered glial function contributes to enhanced eNMDAR-IA coupling in hypertensive rats; and Aim 3- To determine if altered neuronal mechanisms contribute to enhanced eNMDAR-IA coupling in hypertensive rats. We expect this work to expand our knowledge on basic neurobiological principles implicated in the generation of homeostatic neurohumoral responses. More importantly, we expect to identify key pathophysiological brain mechanisms contributing to maldaptive neurohumoral responses in hypertension. We hope our work will help in the development of novel and more efficient therapeutic strategies for the treatment of hypertensive conditions. PUBLIC HEALTH RELEVANCE: Hypertension is a major public health problem in the USA, is characterized by increased activity of the autonomic and neuroendocrine system (neurohumoral activation), which strongly influences morbidity and mortality in these patients. However, the precise mechanisms underlying neurohumoral remain unknown. In this proposal, we will use a multidisciplinary approach to test a series of novel hypothesis that aim to elucidate signaling mechanisms within the central nervous system that contribute to neurohumoral activation in hypertension. We expect our work to provide novel information on mechanisms underlying altered neuronal function in hypertensive patients, and to help in the development of novel and more efficient therapeutic strategies for the treatment of prevalent complications in hypertension.