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: 8116642
• 负责人: COLIN SUMNERS
• 金额: $ 40.45万
• 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/8116642
• 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; acute stress; adenoviral-mediated; age related; blood pressure regulation; hypothalamic-pituitary-adrenal axis; mutant; normotensive; novel; paraventricular nucleus; phenylpyruvate tautomerase; programs; research study

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Current treatment of high blood pressure primarily targets symptoms rather than causes or prevention because the causes of high blood pressure are not established. It is now understood that people who have a high level of stress in their lives and/or react excessively to stress have an increased risk for high blood pressure. The goal of the proposed studies is to show that macrophage migration inhibitory factor in the brain is a key regulator of blood pressure at rest and during stress, thus providing a novel target for the prevention and treatment of high blood pressure.

说明(申请人提供)：已确定中枢神经系统(CNS)通过影响神经内分泌机制和交感神经流出，对健康和疾病的血压进行长期调节。具体地说，基线和应激诱导的下丘脑-垂体-肾上腺(HPA)轴活动和交感神经系统功能的升高与人类高血压的病因学以及包括自发性高血压大鼠(SHR)在内的相关动物模型有关。然而，中枢神经系统调节基线血压和/或应激反应性慢性升高的机制还不够清楚。我们研究计划的总体目标是阐明大脑中调节基线和应激激活血压调节的慢性变化的机制。在这一应用中的实验集中在下丘脑室旁核(PVN)内的调节机制。PVN内的神经元对HPA轴和交感神经系统的中枢调节都是至关重要的，而作用于PVN内的血管紧张素II(Ang II)已成为激活这两种输出的关键神经肽之一。我们最近发现巨噬细胞移动抑制因子(MIF)是Ang II在正常血压大鼠神经元兴奋作用的细胞内负调节因子。总之，我们的研究表明，MIF通过其内在的硫醇蛋白氧化还原酶(TpoR)活性作用于正常血压大鼠的PVN神经元，以减轻Ang II的心血管作用。然而，我们的数据表明，SHR的PVN神经元缺乏这种调节机制，长期在SHR神经元内替代MIF可以钝化这种高血压模型中观察到的与年龄相关的基础血压升高。这些结果证实了MIF在减弱血管紧张素转换酶II的兴奋效应方面的重要作用，血管紧张素转换酶II作用于室旁核，促进与年龄相关的基线血压升高。本申请专门研究PVN MIF在急、慢性应激时血管紧张素Ⅱ介导的血压调节中的作用，并将确定HPA轴和交感神经系统对血压调节的潜在贡献。总体假设是，在SHR的PVN神经元内替换MIF将通过一种需要MIF的TpoR活性的机制来减弱这些动物对应激的血压反应性增加。具体目的是通过利用AAV2介导的基因传递在SHR和正常血压对照组大鼠的PVN神经元中选择性地慢性表达MIF或缺乏TpoR活性的突变MIF蛋白来验证这一假说。这一目标将通过以下具体目标来实现：目的1确定病毒介导的MIF在SHR和正常血压大鼠PVN神经元中的长期表达对急、慢性应激时血压调节的影响。目的2探讨MIF的TpoR部分在介导SHR和正常血压大鼠PVN神经元MIF在急、慢性应激时血压调节中的作用。与公共卫生相关：目前对高血压的治疗主要针对症状，而不是原因或预防，因为高血压的病因尚未确定。现在人们了解到，生活中压力很大和/或对压力反应过度的人患高血压的风险更高。这项研究的目的是证明脑内巨噬细胞移动抑制因子是静息和应激时血压的关键调节因子，从而为高血压的预防和治疗提供新的靶点。