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

基本信息

批准号：
9618915
负责人：
Javier E Stern
金额：
$ 2.36万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9618915
关键词：
CENTRAL NEURONAL GLIAL MECHANISMS NEUROHUMORAL

项目摘要

Abstract 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.

抽象的同情和神经内分泌系统的协调活动对于适当心血管（CV）稳态的维持，持续的交感神经激活高度有害，导致包括高血压在内的简历疾病。因此，阐明机制调节交感神经激活对于预防和更有效的治疗至关重要高血压。下丘脑旁脑室（PVN）核在产生中起关键作用交感的反应。该核内的神经元活性由内在特性和外部突触输入。在最近的研究中，我们表明A型K+ 电流（IA）抑制PVN发射活性，而钝的IA功能有助于增强神经元高血压的活性。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，这两种不同的机制在功能和因果关系上是否是耦合，目前未知。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，支持了外部NMDAR之间的因果关系 IA和IA在高血压中介导增加的神经元活性和交感神经激活时。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。在该提议中，我们将检验以下中心假设，即enmdar的过度激活及其负面活化与IA耦合是神经元活性增加的主要因素，并且高血压中的交感神经激活。此应用的主要目的是表征 ENMDAR-IA耦合的基础信号机制。而且，我们旨在阐明（a）改变神经胶质功能和（b）内在神经元机制对过度活化的相对贡献 enmdar-ia耦合，以及增加的神经元活性和交感神经激活高血压大鼠。使用肾血管高血压动物模型，我们提出以下特定目的：目标1-以表征enmdars和ia之间的功能耦合；瞄准2-确定是否神经胶质功能的改变有助于高血压大鼠的Enmdar-ia耦合增强。并瞄准3至确定改变的神经元机制是否有助于高血压的ENMDAR-IA耦合增强老鼠。我们希望这项工作能够扩展我们对涉及的基本神经生物学原理的知识稳态神经肿瘤反应的产生。更重要的是，我们希望确定关键病理生理的大脑机制有助于导致神经性神经肿瘤反应高血压。我们希望我们的工作将有助于开发新颖，更有效的治疗性治疗高血压疾病的策略。