Stress-induced hypertension and the role of the neuroimmune system

描述(由申请人提供)：T淋巴细胞在高血压的病理生理学中以及最近在心理应激和抑郁症相关的残疾中扮演着重要的角色，这一点已经变得越来越清楚。鉴于慢性心理应激也是高血压发生和维持的一个关键因素，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(S)。中枢神经系统(CNS)在血压调节中起着至关重要的作用，很早就知道它与免疫系统具有双向通讯。最近，我们的研究小组发现，中枢神经系统，尤其是前腹侧第三脑室(AV3V)前脑区，在血管紧张素II诱导的高血压过程中，对周围血管炎症和T细胞的激活起着至关重要的作用。这些研究的结果揭示了对中枢信号、外周炎症和高血压之间联系的新理解。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)是一种头端前脑结构，其独特的位置是整合应激信息，也有神经元投射到参与血压调节的部位，如AV3V区。刺激BNST模拟应激诱导的神经内分泌和自主神经反应，即血压升高、儿茶酚胺增加和促肾上腺皮质激素释放(CRH)释放。在拟议的研究中，我们将研究BNST和CRH在应激性高血压环境中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，这将使我们能够专门识别BNST中产生CRH的细胞，以及删除产生CRH的神经元中的血管紧张素原等基因的能力。我们假设BNST内CRH释放的增加是应激性高血压所必需的，并且这种CRH和BNST在高血压中的参与依赖于T淋巴细胞激活和外周血管炎症。这些研究将为调节高血压等炎症性疾病的中枢和外周机制提供新的信息，并可能为更好地理解压力对心血管疾病发展的负面影响之间的联系提供新的信息。高血压、应激、翻译神经科学和神经免疫学的病理生理学方面的综合专业知识为我们提供了一个进行这项研究的独特机会。 公共卫生相关性：心理应激、高血压和炎症与心血管疾病的进展有关，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变化和外周适应性免疫与前脑中特定的神经激素应激回路有关的假设。这些研究将提供关于应激和炎症影响高血压和心血管疾病发展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.