Paraventricular nucleus regulatory mechanisms in stress and hypertension

描述（由申请方提供）：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，对健康和疾病中的血压进行长期调节。具体而言，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激活的升高与人类和相关动物模型（包括自发性高血压大鼠（SHR））的高血压病因有关。然而，介导基线血压和/或应激反应性慢性升高的CNS机制尚未充分了解。我们研究计划的总体目标是阐明大脑内介导基线和应激激活的血压调节慢性变化的机制。本申请中的实验集中于下丘脑室旁核（PVN）内的调节机制。PVN内的神经元对于HPA轴和交感神经系统的中枢调节是至关重要的，并且在PVN内起作用的血管紧张素II（Ang II）已经成为可以激活这两种输出的一种关键神经肽。我们最近发现，巨噬细胞移动抑制因子（MIF）作为一种细胞内负调节的兴奋作用，血管紧张素II在正常血压大鼠神经元。总的来说，我们的研究表明，MIF行为正常大鼠PVN神经元内通过其固有的巯基蛋白氧化还原酶（TPOR）的活动，以减弱血管紧张素II的心血管作用。然而，我们的数据表明，这种调节机制是不存在的SHR的PVN神经元，并且长期替代SHR神经元内的MIF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。这些结果建立了一个重要的作用，MIF在衰减的兴奋作用的血管紧张素II，作用于PVN，促进年龄相关的基线血压升高。本申请具体研究了PVN MIF在急性和慢性应激期间调节Ang II介导的血压调节中的作用，并且将确定HPA轴和交感神经系统对血压调节的潜在贡献。总的假设是，替换的MIF的PVN神经元的SHR将减弱增加的血压反应性，在这些动物中观察到的压力的机制，需要TPOR活性的MIF。具体目标是通过利用AAV 2介导的基因递送在SHR和正常血压对照大鼠的PVN神经元中选择性地慢性表达MIF或缺乏TPOR活性的突变MIF蛋白来测试这一假设。这一目标将通过以下具体目的实现：目的1是确定病毒介导的MIF在SHR和正常血压大鼠的PVN神经元内的长期表达对急性和慢性应激期间血压调节的影响。目的二是研究MIF的TPOR部分在急性和慢性应激时介导SHR和正常血压大鼠PVN神经元内MIF对血压调节的作用。公共卫生相关性：目前高血压的治疗主要针对症状，而不是原因或预防，因为高血压的原因尚未确定。现在已经知道，生活中压力大和/或对压力反应过度的人患高血压的风险增加。这些研究的目的是证明大脑中的巨噬细胞迁移抑制因子是休息和应激时血压的关键调节因子，从而为预防和治疗高血压提供了一个新的靶点。

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.