Central neuronal-glial mechanisms and neurohumoral activation in hypertension

描述（由申请人提供）：虽然交感和神经内分泌系统的协调活动对于适当维持心血管（CV）稳态至关重要，但持续的交感病理体液激活是非常有害的，会导致包括高血压在内的CV疾病。因此，阐明调节交感体液激活的机制对于预防和更有效地治疗高血压至关重要。下丘脑室旁核（PVN）在交感病理体液反应的产生中起关键作用。这个核内的神经元活动是由内在特性和外在突触输入之间的平衡控制的。在最近的研究中，我们发现a型K+电流（IA）抑制PVN放电活性，IA功能的减弱有助于高血压神经元活性的增强。高血压的另一个主要致病因素是谷氨酸NMDA受体功能增高。然而，这两种不同的机制是否在功能上和因果关系上耦合，目前尚不清楚。通过结合体外和体内研究的多学科方法，我们获得了令人兴奋的初步数据，支持突触外NMDARs和IA在高血压患者中介导神经元活动增加和交感神经激活之间的因果关系。此外，我们发现星形胶质细胞是影响eNMDAR-IA偶联效果的关键参与者。在本提案中，我们将验证eNMDARs的过度激活及其与IA的负耦合是高血压患者神经元活性和交感体液激活增加的主要因素这一中心假设。本应用程序的主要目的是表征eNMDAR-IA耦合的信号机制。此外，我们旨在阐明(a)神经胶质功能改变和(b)内在神经元机制对高血压大鼠eNMDAR-IA偶联过度激活、神经元活性和交感体液激活增加的相对贡献。利用肾血管性高血压动物模型，我们提出以下具体目的：目的1-表征eNMDARs和IA之间的功能耦合；目的2-确定高血压大鼠神经胶质功能改变是否有助于增强eNMDAR-IA偶联；目的3：确定改变的神经元机制是否有助于高血压大鼠eNMDAR-IA偶联增强。我们希望这项工作能够扩展我们对涉及产生稳态神经体液反应的基本神经生物学原理的知识。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脑病理生理机制。我们希望我们的工作将有助于开发新的和更有效的治疗高血压的策略。

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.