Central neuronal-glial mechanisms and neurohumoral activation in hypertension

高血压的中枢神经元神经胶质机制和神经体液激活

• 批准号: 8477277
• 负责人: Javier E Stern
• 金额: $ 35.7万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477277
• 关键词: Address; Angiotensin II; Animal Model; Astrocytes; Brain; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Coupled; Coupling; Data; Development; Equilibrium; Generations; Glutamates; Homeostasis; Hypertension; Hypothalamic structure; In Vitro; Knowledge; Link; Maintenance; Mediating; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurobiology; Neurons; Neurosecretory Systems; Patients; Play; Prevention; Principal Investigator; Property; Public Health; Rattus; Relative (related person); Role; Series; Signal Transduction; Source; Sympathetic Nervous System; Synapses; Testing; Therapeutic; Work; hypertension treatment; in vivo; interdisciplinary approach; kidney vascular structure; mortality; novel; paraventricular nucleus; receptor function; response; treatment strategy

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.

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）稳态至关重要，但持续的交感体液激活非常有害，会导致包括高血压在内的心血管疾病。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）在交感体液反应的产生中起着关键作用。该核内的神经元活动由内在特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 K+ 电流 (IA) 抑制 PVN 放电活动，而 IA 功能减弱有助于增强高血压的神经元活动。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 NMDAR 和 IA 在介导高血压神经元活动增加和交感神经激活方面存在因果关系。此外，我们发现星形胶质细胞是影响 eNMDAR-IA 耦合功效的关键参与者。在本提案中，我们将测试中心假设，即 eNMDAR 的过度激活及其与 IA 的负耦合是高血压神经元活动增加和交感体液激活的主要促成因素。该应用的主要目标是表征 eNMDAR-IA 耦合背后的信号机制。此外，我们的目的是阐明（a）神经胶质功能改变和（b）内在神经元机制对 eNMDAR-IA 偶联过度激活以及高血压大鼠神经元活动和交感体液激活增加的相对贡献。 使用肾血管性高血压动物模型，我们提出以下具体目标： 目标 1- 表征 eNMDAR 和 IA 之间的功能耦合；目标 2-确定神经胶质功能的改变是否有助于增强高血压大鼠的 eNMDAR-IA 偶联；目标 3-确定改变的神经元机制是否有助于增强高血压大鼠的 eNMDAR-IA 耦合。我们期望这项工作能够扩展我们对与稳态神经体液反应的产生有关的基本神经生物学原理的了解。更重要的是，我们期望确定导致高血压适应不良神经体液反应的关键病理生理学大脑机制。我们希望我们的工作将有助于开发治疗高血压疾病的新颖且更有效的治疗策略。