Paraventricular nucleus regulatory mechanisms in stress and hypertension

6.项目摘要/摘要 已确定中枢神经系统(CNS)对血液的长期调节有贡献 通过对神经内分泌机制和交感神经流出的影响，健康和疾病中的压力。 具体地说，基线的升高和应激诱导的下丘脑-垂体-肾上腺(HPA)的激活 轴活动和交感神经系统功能与人类高血压的病因学有关 以及包括自发性高血压大鼠(SHR)在内的相关动物模型。然而，中枢神经系统机制 调节基线血压和/或应激反应的慢性升高的机制还没有得到充分的了解。 我们研究计划的总体目标是阐明大脑内调节慢性疾病的机制 基线和应激激活血压调节的变化。此应用程序中的实验重点 关于下丘脑室旁核(PVN)内的调节机制。大脑中的神经元 室旁核对HPA轴和交感神经系统的中枢调节都是关键的，并且 血管紧张素II(Ang II)作用于室旁核，已成为一种关键的神经肽，可激活 这些输出。我们最近发现巨噬细胞移动抑制因子(MIF)是一种细胞内的 血管紧张素转换酶II对正常血压大鼠神经元兴奋作用的负调节作用。总而言之，我们的研究 提示MIF通过其固有的硫醇蛋白氧化还原酶作用于正常血压大鼠的下丘脑室旁核神经元。 (TpoR)活性以减弱Ang II的心血管作用。然而，我们的数据表明这一调节 SHR的PVN神经元缺乏这种机制，MIF在SHR神经元内的长期替代 钝化在这种高血压模型中观察到的与年龄相关的基线血压上升。这些 结果MIF在减弱Ang II的兴奋作用中起重要作用，作用于PVN内， 促进与年龄相关的基线血压上升。本申请具体研究 PVN MIF在血管紧张素Ⅱ介导的急、慢性血压调节中的作用 应激，以及HPA轴和交感神经系统对血压的潜在贡献 监管将会确定。总体假设是SHR室旁核神经元内MIF的替代。 会减弱在这些动物中观察到的血压对应激反应的增加，其机制是 需要MIF的TpoR活动。具体目标是利用aav2介导的基因来验证这一假说。 在PVN中选择性地慢性表达MIF或缺乏TpoR活性的突变MIF蛋白 自发性高血压大鼠和正常血压对照组大鼠神经元。这一目标将通过以下具体目标实现：目标 一是确定病毒介导的MIF在自发性高血压大鼠和大鼠PVN神经元中的长期表达的影响。 正常血压大鼠在急、慢性应激过程中的血压调节。目标2是确定角色 MIF的TpoR部分在介导MIF对SHR和正常血压大鼠PVN神经元影响中的作用 关于急、慢性应激时的血压调节。

6. Project Summary/Abstract It is established that the central nervous system (CNS) contributes to the long-term regulation of blood pressure in both health and disease via effects on neuroendocrine mechanisms and sympathetic outflow. Specifically, elevations in baseline and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis activity and sympathetic nervous system function are implicated in the etiology of hypertension in humans and in related animal models including the spontaneously hypertensive rat (SHR). However, CNS mechanisms that mediate chronic increases in baseline blood pressure and/or stress reactivity are inadequately understood. The overall goal of our research program is to elucidate mechanisms within the brain that mediate chronic changes in baseline and stress-activated blood pressure regulation. The experiments in this application focus on regulatory mechanisms within the paraventricular nucleus (PVN) of the hypothalamus. Neurons within the PVN are critical to the central regulation of both the HPA axis and the sympathetic nervous system, and angiotensin II (Ang II) acting within the PVN has emerged as one key neuropeptide that can activate both of these outputs. We have recently identified macrophage migration inhibitory factor (MIF) as an intracellular negative regulator of the excitatory actions of Ang II in normotensive rat neurons. Collectively, our studies indicate that MIF acts within PVN neurons of normotensive rats via its intrinsic thiol protein oxidoreductase (TPOR) activity to attenuate the cardiovascular actions of Ang II. However, our data indicate this regulatory mechanism is absent from PVN neurons of SHR, and that long-term replacement of MIF within SHR neurons blunts the age-related increase in baseline blood pressure observed in this model of hypertension. These results establish an important role for MIF in attenuating the excitatory effects of Ang II, acting within the PVN, to promote age-related increases in baseline blood pressure. The present application specifically investigates the role of PVN MIF in the modulation of Ang II-mediated blood pressure regulation during acute and chronic stress, and potential contributions of both the HPA axis and the sympathetic nervous system to blood pressure regulation will be determined. The overall hypothesis is that replacement of MIF within PVN neurons of SHR will attenuate the increased blood pressure reactivity to stress observed in these animals by a mechanism that requires the TPOR activity of MIF. The specific goal is to test this hypothesis by utilizing AAV2-mediated gene delivery to chronically express MIF, or a mutant MIF protein that lacks TPOR activity, selectively in PVN neurons of SHR and normotensive control rats. This goal will be achieved via the following Specific Aims: Aim 1 is to determine the effects of long-term viral-mediated expression of MIF within PVN neurons of SHR and normotensive rats on blood pressure regulation during acute and chronic stress. Aim 2 is to determine the role of the TPOR moiety of MIF in mediating the effects of MIF within PVN neurons of SHR and normotensive rats on blood pressure regulation during acute and chronic stress.