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: 7903187
• 负责人: COLIN SUMNERS
• 金额: $ 40.86万
• 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/7903187
• 关键词: Acute; Adrenal Glands; 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; Life; Long-Term Effects; Mediating; Migration Inhibitory Factor; Modeling; Molecular; Nervous System Physiology; Neuraxis; Neurons; Neuropeptides; Neurosecretory Systems; Output; Oxidoreductase; Pituitary Gland; Prevention; Property; Proteins; Rattus; Reactive Oxygen Species; Regulation; Research; Rest; Risk; Role; Stress; Sulfhydryl Compounds; Sympathetic Nervous System; Symptoms; Testing; Viral; adenoviral-mediated; age related; blood pressure regulation; hypothalamic-pituitary-adrenal axis; mutant; normotensive; novel; paraventricular nucleus; phenylpyruvate tautomerase; programs; public health relevance; 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.

描述（由申请人提供）：确定中枢神经系统（CNS）通过对神经内分泌机制和交感神经流出的影响来促进健康和疾病中血压的长期调节。具体而言，基线和应力诱导的下丘脑 - 垂体 - 肾上腺（HPA）轴活动和交感神经系统功能的激活与人类和相关动物模型的高血压病因有关，包括自发性高度高性大鼠（SHR）。但是，介导基线血压和/或应激反应性慢性增加的中枢神经系统机制是不充分理解的。我们的研究计划的总体目标是阐明大脑内的机制，以介导基线和压力激活的血压调节的慢性变化。该应用中的实验集中于下丘脑室室核（PVN）内的调节机制。 PVN中的神经元对于HPA轴和交感神经系统的中心调节至关重要，而在PVN中作用的血管紧张素II（ANG II）已成为一种可以激活这两个输出的关键神经肽。我们最近将巨噬细胞迁移抑制因子（MIF）确定为正常大鼠神经元中ANG II兴奋性作用的细胞内负调节剂。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（TPOR）活性在正常大鼠的PVN神经元内作用，以减轻ANG II的心血管作用。但是，我们的数据表明，SHR的PVN神经元没有这种调节机制，而SHR神经元内MIF的长期替代使这种高血压模型中观察到的基线血压的增加相关。这些结果确定了MIF在衰减PVN内的ANG II的兴奋作用方面的重要作用，以促进基线血压与年龄相关的增加。本应用专门研究了PVN MIF在急性和慢性应激过程中ANG II介导的血压调节调节调节中的作用，以及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将通过需要MIF的TPOR活性的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。具体的目标是通过利用AAV2介导的基因递送到慢性表达MIF或缺乏TPOR活性的突变型MIF蛋白，在SHR和正常对照大鼠的PVN神经元中选择性地检验该假设。该目标将通过以下特定目的实现：目标1是确定MIF在SHR和正常大鼠PVN神经元中长期病毒介导的表达对急性和慢性应激期间血压调节的影响。目的2是确定MIF的Tpor部分在SHR和正常大鼠PVN神经元中介导MIF在急性和慢性应激期间血压调节的作用。公共卫生相关性：当前高血压治疗主要针对症状，而不是原因或预防，因为没有建立高血压的原因。现在可以理解，生活中压力很高和/或对压力过度反应的人会增加高血压的风险。拟议的研究的目的是表明大脑中的巨噬细胞迁移抑制因子是静止和压力期间血压的关键调节剂，因此为预防和治疗高血压提供了新的目标。