Stress-induced hypertension and the role of the neuroimmune system

压力诱发的高血压和神经免疫系统的作用

• 批准号: 8803802
• 负责人: Paul J Marvar
• 金额: $ 24.87万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803802
• 关键词: Address; Adrenal Glands; Adult; Affect; American; Amygdaloid structure; Angiotensin II; Angiotensin Type 1a Receptor; Angiotensinogen; Angiotensins; Atherosclerosis; Behavioral; Blood - brain barrier anatomy; Blood Pressure; Brain; Brain Stem; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cell Nucleus; Cells; Chronic; Communication; Corticotropin-Releasing Hormone; DOCA; Data; Development; Disease; Disease Progression; Epidemiology; Functional disorder; Genes; Heart Rate; Homeostasis; Hormones; Hypertension; Hypothalamic structure; Immune Cell Activation; Immune System Diseases; Immune System and Related Disorders; Immune system; Inflammation; Inflammatory; Laboratories; Lesion; Life; Link; Liquid substance; Lymphocyte Activation; Maintenance; Mediating; Mental Depression; Midbrain structure; Mus; Neuraxis; Neuroimmunomodulation; Neurons; Neuropeptides; Neurosecretory Systems; Norepinephrine; Nucleus solitarius; Organ; Pathogenesis; Peptides; Peripheral; Physiological; Pituitary Gland; Plasma; Play; Positioning Attribute; Production; Prosencephalon; Psychological Stress; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Societies; Stimulus; Stress; Stroke; Structure; Structure of terminal stria nuclei of preoptic region; Subfornical Organ; System; T-Cell Activation; T-Lymphocyte; Technology; Testing; Third ventricle structure; Tissues; Transgenic Organisms; Viral Vector; adaptive immunity; biological adaptation to stress; blood pressure regulation; disability; interdisciplinary approach; neural circuit; neuroimmunology; neurotransmission; novel; organum vasculosum of the lamina terminalis; paraventricular nucleus; relating to nervous system; response; salt sensitive hypertension; translational neuroscience; vascular inflammation

It has been become increasingly clear that T lymphocytes play an important role in the pathophysiology of hypertension and more recently in psychological stress and depression related disabilities. Given that chronic psychological stress is also a key contributing factor to the development and maintenance of hypertension, further understanding of the adaptive immune response and the underlying neuroimmune mechanism(s) is warranted. The central nervous system (CNS) plays an essential role in the regulation of blood pressure and has long been known to have bi-directional communication with the immune system. Recently our group has shown that the CNS, in particular the anteroventral third ventricle (AV3V) forebrain region, is critical for the development of peripheral vascular inflammation and T cell activation during angiotensin II-induced hypertension. The results of these studies reveal a new understanding for the link between central signals, peripheral inflammation and hypertension. In the proposed studies we plan to investigate the role of the adaptive immune response in stress-induced hypertension and to further characterize the underlying neurocircuitry. The bed nucleus of the stria terminalis (BNST) is a rostral forebrain structure that is uniquely positioned to integrate stress information and also has neurons that project to the sites involved in blood pressure regulation such as the AV3V region. Stimulation of the BNST mimics stress-induced neuroendocrine and autonomic responses, i.e. elevation of blood pressure, increased catecholamines and corticotropin-releasing hormone (CRH) release. In the proposed studies, we will investigate the role of BNST and CRH in blood pressure regulation and peripheral vascular inflammation in a setting of stress-induced hypertension. Using Cre-lox technology, we plan to use genetically modified mice that will allow us to specifically identify CRH producing cells in the BNST as well as the ability to delete genes such as angiotensinogen in CRH producing neurons. We hypothesize that increased CRH release within the BNST is required for stress-induced hypertension and that this CRH- and BNST involvement in hypertension is dependent on increased T lymphocyte activation and peripheral vascular inflammation. These studies will provide new information for the central and peripheral mechanisms that mediate inflammatory diseases such as hypertension and may provide a better understanding for the link between the negative impact of stress on cardiovascular disease development. The combined expertise in the pathophysiology of hypertension, stress, translational neuroscience and neuroimmunology afford us a unique opportunity to pursue this research.

人们越来越清楚 T 淋巴细胞在 高血压的病理生理学以及最近的心理压力和抑郁症 相关的残疾。鉴于长期的心理压力也是导致抑郁症的一个关键因素 高血压的发生和维持，进一步了解适应性 免疫反应和潜在的神经免疫机制是必要的。中央 神经系统（CNS）在血压调节中发挥着重要作用，长期以来 已知与免疫系统有双向通讯。最近我们组 研究表明，中枢神经系统，特别是前腹侧第三脑室（AV3V）前脑区域， 对于周围血管炎症的发生和 T 细胞活化至关重要 血管紧张素II诱发的高血压。这些研究结果揭示了新的认识 研究中枢信号、外周炎症和高血压之间的联系。在提议的 我们计划研究适应性免疫反应在应激诱导中的作用 高血压并进一步表征潜在的神经回路。床核 终纹（BNST）是一种前脑头侧结构，具有独特的位置来整合 压力信息，还有投射到与血压有关的部位的神经元 调节，例如 AV3V 区域。 BNST 的刺激模拟应激诱导的 神经内分泌和自主反应，即血压升高，增加 儿茶酚胺和促肾上腺皮质激素释放激素（CRH）的释放。在拟议的研究中， 我们将研究BNST和CRH在血压调节和外周血中的作用 应激性高血压中的血管炎症。使用 Cre-lox 技术，我们 计划使用转基因小鼠，这将使我们能够专门识别产生 CRH 的 BNST 中的细胞以及删除 CRH 中血管紧张素原等基因的能力 产生神经元。我们假设 BNST 内需要增加 CRH 释放 对于应激性高血压，CRH 和 BNST 参与高血压是 依赖于 T 淋巴细胞活化增加和外周血管炎症。这些 研究将为介导的中枢和外周机制提供新信息 高血压等炎症性疾病可能有助于更好地理解这种联系 压力对心血管疾病发展的负面影响。合并后的 高血压病理生理学、压力、转化神经科学和 神经免疫学为我们提供了进行这项研究的独特机会。