Paraventricular nucleus regulatory mechanisms in stress and hypertension

6.项目总结/摘要 中枢神经系统（CNS）有助于血液的长期调节 通过对神经内分泌机制和交感神经流出的影响，在健康和疾病中产生压力。 具体而言，基线升高和应激诱导的下丘脑-垂体-肾上腺（HPA）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 以及在包括自发性高血压大鼠（SHR）在内的相关动物模型中。然而，CNS机制 介导基线血压和/或应激反应性慢性增加的机制还不充分。 我们研究计划的总体目标是阐明大脑内介导慢性炎症的机制。 基线和应激激活的血压调节的变化。在此应用中的实验重点是 下丘脑室旁核（PVN）内的调节机制。内神经元 PVN对HPA轴和交感神经系统的中枢调节至关重要， 在PVN内起作用的血管紧张素II（Ang II）已经成为一种关键的神经肽，其可以激活 这些产出。我们最近发现巨噬细胞移动抑制因子（MIF）作为一种细胞内的 在正常血压大鼠神经元中，Ang II兴奋作用的负调节剂。总的来说，我们的研究 表明MIF通过其内在巯基蛋白氧化还原酶在正常血压大鼠PVN神经元内起作用 （TPOR）活性以减弱Ang II的心血管作用。然而，我们的数据表明， SHR室旁核神经元缺乏这种机制， 减弱了在该高血压模型中观察到的基线血压的年龄相关性增加。这些 结果确定了MIF在减弱Ang II的兴奋作用中的重要作用，作用于PVN内， 促进与年龄相关的基线血压升高。本申请具体地研究了 室旁核MIF在急性和慢性高血压时调节血管紧张素II介导的血压中的作用 压力，以及HPA轴和交感神经系统对血压的潜在贡献 规则将被确定。总体假设是，SHR室旁核神经元内MIF的替代 将通过一种机制减弱在这些动物中观察到的对压力的升高的血压反应性， 需要MIF的TPOR活性。具体目标是通过利用AAV 2介导的基因转染来验证这一假设。 在PVN中选择性地长期表达MIF或缺乏TPOR活性的突变MIF蛋白的递送 SHR和正常血压对照大鼠的神经元。这一目标将通过以下具体目标实现： 1是确定病毒长期介导的MIF在SHR PVN神经元内表达的影响， 正常血压大鼠在急性和慢性应激时血压调节的作用。目标2：确定角色 MIF的TPOR部分介导MIF在SHR和正常血压大鼠PVN神经元内的作用 在急性和慢性压力下的血压调节。

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.