Paraventricular nucleus regulatory mechanisms in stress and hypertension

应激和高血压的室旁核调节机制

• 批准号: 8476247
• 负责人: COLIN SUMNERS
• 金额: $ 38.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476247
• 关键词: Angiotensin II; Animal Model; Animals; Antioxidants; Attenuated; Blood Pressure; Brain; Cardiovascular system; Chronic; Chronic stress; Data; Disease; Etiology; Gene Delivery; Goals; Health; Human; Hypertension; Hypothalamic structure; Inbred SHR Rats; Long-Term Effects; Mediating; Migration Inhibitory Factor; Modeling; Molecular; Nervous System Physiology; Neuraxis; Neurons; Neuropeptides; Neurosecretory Systems; Output; Oxidoreductase; Prevention; Property; Proteins; Rattus; Reactive Oxygen Species; Regulation; Research; Rest; Risk; Role; Stress; Sulfhydryl Compounds; Sympathetic Nervous System; Symptoms; Testing; Viral; abstracting; acute stress; adenoviral-mediated; age related; blood pressure regulation; hypothalamic-pituitary-adrenal axis; mutant; normotensive; novel; paraventricular nucleus; phenylpyruvate tautomerase; programs; research study

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.

6. 项目总结/摘要 已确定中枢神经系统（CNS）有助于血液的长期调节 通过影响神经内分泌机制和交感神经流出而给健康和疾病带来压力。 具体来说，基线升高和压力诱导的下丘脑-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有关 以及相关的动物模型，包括自发性高血压大鼠（SHR）。 However, CNS mechanisms 介导基线血压和/或应激反应性慢性升高的机制尚不清楚。 我们研究计划的总体目标是阐明大脑内介导慢性疾病的机制 基线和压力激活血压调节的变化。本应用中的实验重点 下丘脑室旁核（PVN）内的调节机制。 Neurons within the PVN 对 HPA 轴和交感神经系统的中枢调节至关重要，并且 作用于 PVN 的血管紧张素 II (Ang II) 已成为一种关键的神经肽，可以激活 these outputs.我们最近发现巨噬细胞迁移抑制因子（MIF）是一种细胞内 正常血压大鼠神经元中 Ang II 兴奋作用的负调节因子。总的来说，我们的研究 表明 MIF 通过其内在的硫醇蛋白氧化还原酶在正常血压大鼠的 PVN 神经元内发挥作用 (TPOR) 活性可减弱 Ang II 的心血管作用。然而，我们的数据表明这种监管 SHR 的 PVN 神经元不存在这种机制，并且 SHR 神经元内的 MIF 长期替代 抑制在该高血压模型中观察到的与年龄相关的基线血压升高。这些 结果确定了 MIF 在减弱 Ang II 的兴奋作用方面发挥着重要作用，作用于 PVN， 促进与年龄相关的基线血压升高。本申请具体研究了 PVN MIF 在调节 Ang II 介导的急性和慢性血压调节中的作用 压力以及 HPA 轴和交感神经系统对血压的潜在影响 监管将被确定。总体假设是 SHR 的 PVN 神经元内 MIF 的替代 将通过以下机制减弱在这些动物中观察到的血压对压力的反应性增加： 需要 MIF 的 TPOR 活性。具体目标是利用 AAV2 介导的基因来检验这一假设 选择性地在 PVN 中递送长期表达的 MIF 或缺乏 TPOR 活性的突变型 MIF 蛋白 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来实现： 目标 图1是确定SHR和PVN神经元内长期病毒介导的MIF表达的影响 正常血压大鼠在急性和慢性应激期间的血压调节。目标2是确定角色 MIF 的 TPOR 部分介导 SHR 和正常血压大鼠 PVN 神经元内 MIF 的作用 急性和慢性应激期间的血压调节。