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: 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
• 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

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 虽然交感神经系统和神经内分泌系统的协调活动对于正常的生理活动至关重要。 维持心血管（CV）稳态，持续的交感体液激活是高度 有害，导致包括高血压在内的心血管疾病。因此，阐明机制 调节交感体液激活对于预防和更有效地治疗 高血压。下丘脑室旁核（PVN）在神经元的产生中起着关键作用 交感体液反应。该核内的神经元活动由之间的平衡控制 内在属性和外在突触输入。在最近的研究中，我们表明 A 型 K+ 电流 (IA) 抑制 PVN 放电活动，IA 功能减弱有助于增强神经元 高血压活动。高血压的另一个主要致病因素是谷氨酸NMDA升高 受体功能。然而，这两种不同的机制在功能上和因果上是否有效？ 耦合，目前未知。采用结合体外和体内的多学科方法 研究中，我们获得了令人兴奋的初步数据，支持突触外 NMDAR 之间的因果关系 和 IA 介导高血压神经元活动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 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 的过度激活及其负面影响 与 IA 的耦合是神经元活动增加的一个主要促成因素 高血压中的交感体液激活。该应用程序的主要目标是表征 eNMDAR-IA 耦合的信号传导机制。此外，我们的目的是阐明 (a) 神经胶质功能改变和 (b) 内在神经元机制对过度激活的相对贡献 eNMDAR-IA 耦合，并增加神经元活动和交感体液激活 高血压大鼠。使用肾血管性高血压动物模型，我们提出以下具体建议 目标：目标 1 - 表征 eNMDAR 和 IA 之间的功能耦合；目标 2 - 确定是否 神经胶质功能的改变有助于增强高血压大鼠的 eNMDAR-IA 耦合；和目标 3- 至 确定改变的神经元机制是否有助于增强高血压中的 eNMDAR-IA 耦合 老鼠。我们希望这项工作能够扩展我们对与神经生物学相关的基本神经生物学原理的了解。 稳态神经体液反应的产生。更重要的是，我们希望找到关键的 导致适应不良的神经体液反应的病理生理学脑机制 高血压。我们希望我们的工作将有助于开发新颖且更有效的治疗方法 治疗高血压的策略。

项目成果

A-type K+ channels contribute to the prorenin increase of firing activity in hypothalamic vasopressin neurosecretory neurons.

A 型 K 通道有助于下丘脑加压素神经分泌神经元中肾素原的放电活动增加。

• 发表时间: 2017-09-01
• 作者: Pitra, Soledad;Stern, Javier E
• 通讯作者: Stern, Javier E

Neuroendocrine-autonomic integration in the paraventricular nucleus: novel roles for dendritically released neuropeptides.

室旁核中的神经内分泌自主整合：树突状释放的神经肽的新作用。

• 发表时间: 2015-06
• 影响因子: 3.2
• 作者: Stern; J E
• 通讯作者: J E

Compromised blood-brain barrier permeability: novel mechanism by which circulating angiotensin II signals to sympathoexcitatory centres during hypertension.

血脑屏障通透性受损：高血压期间循环血管紧张素 II 向交感兴奋中心发出信号的新机制。

• 发表时间: 2016-03-15
• 作者: Biancardi, V C;Stern, J E
• 通讯作者: Stern, J E

Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior.

大脑先天免疫调节下丘脑弓状神经元活动和进食行为。

• DOI: 10.1210/en.2014-1849
• 发表时间: 2015-02-03
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: W. Reis;C. Yi;Yuanqing Gao;M. H. Tschöp;J. Stern
• 通讯作者: J. Stern

A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity.

突触外 NMDA 受体与星形胶质细胞控制下的 A 型 K 通道之间的功能耦合可调节下丘脑神经分泌神经元活动。

• 发表时间: 2014-07-01
• 作者: Naskar, Krishna;Stern, Javier E
• 通讯作者: Stern, Javier E