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: 8293201
• 负责人: COLIN SUMNERS
• 金额: $ 40.26万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293201
• 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; 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。项目摘要/摘要 已经确定中枢神经系统（CNS）有助于长期调节血液 健康和疾病的压力都通过对神经内分泌机制和交感神经流出的影响。 具体而言，基线和应力诱导的下丘脑 - 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有关 在相关的动物模型中，包括自发高血压大鼠（SHR）。但是，CNS机制 这种介导的基线血压和/或应激反应性的慢性增加不足。 我们研究计划的总体目标是阐明大脑中介导慢性的机制 基线和应力激活的血压调节变化。该应用程序重点的实验 关于下丘脑室室核（PVN）内的调节机制。神经元内的神经元 PVN对于HPA轴和交感神经系统的中心调节至关重要，以及 血管紧张素II（ANG II）作用在PVN内已成为一种关键的神经肽，可以激活两种 这些输出。我们最近确定巨噬细胞迁移抑制因子（MIF）为细胞内 ANG II在正常大鼠神经元中的兴奋作用的负调节剂。总体而言，我们的研究 表明MIF通过其内在的硫醇氧化还原酶在正常大鼠的PVN神经元内作用 （TPOR）衰减ANG II的心血管作用的活性。但是，我们的数据表明了这种监管 SHR的PVN神经元不存在机制，而SHR神经元内的长期替代了MIF 在这种高血压模型中观察到的基线血压与年龄相关的增加。这些 结果确定了MIF在衰减ANG II的兴奋作用方面的重要作用，该作用在PVN内， 为了促进与年龄有关的基线血压增加。本申请专门研究 PVN MIF在急性和慢性期间调节ANG II介导的血压调节的作用 HPA轴和交感神经系统对血压的压力和潜在贡献 法规将被确定。总体假设是在SHR的PVN神经元内替换MIF 将通过一种机制来减轻这些动物中观察到的压力的血压反应性的增加 需要MIF的TPOR活性。具体目标是通过利用AAV2介导的基因检验这一假设 在PVN中选择性地递送至慢性表达MIF或缺乏TPOR活性的突变MIF蛋白 SHR和正常控制大鼠的神经元。该目标将通过以下特定目的实现：目标 1是确定MIF在SHR和SHR和 急性和慢性应激期间血压调节的正常大鼠。目标2是确定角色 MIF的TPOR部分在SHR和正常大鼠的PVN神经元中介导MIF的作用 急性和慢性应激期间的血压调节。