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: 8669816
• 负责人: Javier E Stern
• 金额: $ 36.75万
• 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/8669816
• 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，但持续的交感神经激活却是高度有害的，对包括高血压在内的CV疾病有害。因此，阐明调节交感神经激活的机制对于预防和更有效的高血压治疗至关重要。下丘脑室室（PVN）核在交感神经反应的产生中起关键作用。该核内的神经元活性受内在特性和外部突触输入之间的平衡控制。在最近的研究中，我们表明A型K+电流（IA）抑制了PVN发射活性，并且钝化的IA功能有助于增强高血压神经元活性。高血压的另一个主要致病因素是增加谷氨酸NMDA受体功能。但是，目前尚不清楚这两种不同的机制在功能和因果关系上是否具有因果关系。使用多学科方法结合体外和体内研究，我们获得了令人兴奋的初步数据，该数据支持介导神经元活性增加的神经元活性和高血压中的交感神经激活，以介导外突触性NMDAR和IA之间的因果关系。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。在该提案中，我们将检验以下中心假设：ENMDAR的过度激活及其与IA的负耦合是神经元活性增加的主要因素，而高血压中的交感神经运动。该应用程序的主要目的是表征ENMDAR-IA耦合的信号传导机制。此外，我们旨在阐明（a）神经胶质功能改变的相对贡献和（b）内在的神经元机制对ENMDAR-IA偶联的过度激活，以及高血压大鼠中神经元活性和交感神经激活的增加。 使用肾血管高血压动物模型，我们提出了以下特定目的：目标1-以表征enmdars和ia之间的功能耦合；目标2-确定神经胶质功能是否有助于高血压大鼠的Enmdar-ia耦合增强；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。我们希望这项工作能够扩展我们对涉及稳态神经肿瘤反应的基本神经生物学原理的知识。更重要的是，我们期望确定关键的病理生理大脑机制，导致高血压中有助于神经性神经肿瘤反应。我们希望我们的工作将有助于开发新颖，更有效的治疗策略，以治疗高血压疾病。