Stress-induced hypertension and the role of the neuroimmune system

描述（由申请人提供）：越来越清楚的是，T淋巴细胞在高血压的病理生理学中起重要作用，最近在心理应激和抑郁相关残疾中起重要作用。鉴于慢性心理应激也是高血压发展和维持的一个关键因素，因此有必要进一步了解适应性免疫反应和潜在的神经免疫机制。中枢神经系统（CNS）在血压调节中起着至关重要的作用，并且长期以来一直被认为与免疫系统具有双向通信。最近，我们的小组已经表明，中枢神经系统，特别是前腹侧第三脑室（AV 3V）前脑区，是血管紧张素II诱导的高血压期间外周血管炎症和T细胞活化的发展至关重要。这些研究结果揭示了中枢信号、外周炎症和高血压之间联系的新认识。在拟议的研究中，我们计划调查适应性免疫反应在应激性高血压中的作用，并进一步表征潜在的神经回路。终纹床核（BNST）是一个吻侧前脑结构，它独特地定位于整合压力信息，并且还具有投射到血压调节所涉及的部位（如AV 3V区域）的神经元。刺激BNST模拟应激诱导的神经内分泌和自主反应，即血压升高、增加的儿茶酚胺和促肾上腺皮质激素释放激素（CRH）释放。在本研究中，我们将探讨BNST和CRH在应激性高血压的血压调节和外周血管炎症中的作用。使用Cre-lox技术，我们计划使用转基因小鼠，这将使我们能够特异性地识别BNST中产生CRH的细胞，以及删除CRH产生神经元中血管紧张素原等基因的能力。我们假设，增加CRH释放内BNST是必要的应激性高血压，这CRH和BNST参与高血压是依赖于增加T淋巴细胞活化和外周血管炎症。这些研究将为介导高血压等炎症性疾病的中枢和外周机制提供新的信息，并可能更好地了解压力对心血管疾病发展的负面影响之间的联系。高血压，应激，转化神经科学和神经免疫学的病理生理学的综合专业知识为我们提供了一个独特的机会来进行这项研究。 公共卫生相关性：心理应激、高血压和炎症与心血管疾病进展有关，但中枢和外周机制尚不清楚。这个项目将测试压力引起的血压和外周适应性免疫变化与前脑中特定神经激素压力回路有关的假设。这些研究将提供关于压力和炎症对高血压和心血管疾病发展的影响的中枢和外周机制的新信息。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Psychological stress, hypertension and inflammation have been linked to cardiovascular disease progression, however the central and peripheral mechanisms are unclear. This project will test the hypothesis that stress induced changes in blood pressure and peripheral adaptive immunity are linked to specific neurohormonal stress circuits in the forebrain. These studies will provide new information regarding the central and peripheral mechanisms for the impact of stress and inflammation on hypertension and cardiovascular disease development.