Central neuronal-glial mechanisms and neurohumoral activation in hypertension

描述（由申请方提供）：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，可导致CV疾病，包括高血压。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，并且IA功能的钝化有助于高血压时神经元活动的增强。高血压的另一个主要致病因素是谷氨酸NMDA受体功能增加。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。使用多学科的方法结合在体外和体内的研究，我们获得了令人兴奋的初步数据，支持突触外NMDAR和IA之间的因果关系，在介导增加的神经元活动和交感神经激活高血压。此外，我们发现星形胶质细胞是影响eNMDAR-IA偶联的功效的关键参与者。在这项提议中，我们将测试的核心假设，过度激活eNMDAR和其负耦合IA是一个主要的因素，增加神经元活动和交感体液激活高血压。本申请的主要目的是表征eNMDAR-IA偶联背后的信号传导机制。此外，我们的目的是阐明相对贡献（a）改变胶质细胞功能和（B）内在神经元机制过度激活的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，我们提出以下具体目的：目的1-表征eNMDARs和IA之间的功能偶联;目的2-确定是否改变的胶质细胞功能有助于增强高血压大鼠的eNMDAR-IA偶联;目的3-确定是否改变的神经元机制有助于增强高血压大鼠的eNMDAR-IA偶联。我们希望这项工作，以扩大我们的基本神经生物学原理的知识，涉及到产生的稳态神经体液反应。更重要的是，我们希望确定关键的病理生理脑机制，有助于适应性神经体液反应在高血压。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疾病的治疗策略。 公共卫生相关性：高血压是美国的一个主要公共卫生问题，其特征在于自主神经和神经内分泌系统（神经体液激活）的活动增加，这强烈影响这些患者的发病率和死亡率。然而，神经体液的确切机制仍不清楚。在这个建议中，我们将使用多学科的方法来测试一系列新的假设，旨在阐明中枢神经系统内的信号机制，有助于高血压的神经体液激活。我们希望我们的工作提供新的信息机制改变神经元功能的高血压患者，并帮助开发新的和更有效的治疗策略，治疗高血压的常见并发症。

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.