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以及最近在心理压力和抑郁相关的残疾中发挥着重要作用。鉴于慢性心理压力也是高血压发生和维持的关键因素，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）在血压调节中发挥着重要作用，长期以来人们都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，特别是第三脑室前腹侧 (AV3V) 前脑区域，对于血管紧张素 II 诱导的高血压期间外周血管炎症和 T 细胞激活的发生至关重要。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认识。在拟议的研究中，我们计划研究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) 是一种前脑头侧结构，具有独特的位置来整合压力信息，并且还具有投射到涉及血压调节的部位（例如 AV3V 区域）的神经元。 BNST 的刺激模拟压力引起的神经内分泌和自主反应，即血压升高、儿茶酚胺和促肾上腺皮质激素释放激素 (CRH) 释放增加。在拟议的研究中，我们将研究 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。利用 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识别 BNST 中产生 CRH 的细胞，并能够删除产生 CRH 的神经元中的血管紧张素原等基因。我们假设 BNST 内 CRH 释放增加是应激性高血压所必需的，并且 CRH 和 BNST 参与高血压取决于 T 淋巴细胞活化增加和外周血管炎症。这些研究将为介导高血压等炎症性疾病的中枢和外周机制提供新信息，并可能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。高血压病理生理学、压力、转化神经科学和神经免疫学的综合专业知识为我们提供了开展这项研究的独特机会。 公共卫生相关性：心理压力、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。该项目将检验以下假设：压力引起的血压和外周适应性免疫的变化与前脑中特定的神经激素压力回路有关。这些研究将提供有关压力和炎症对高血压和心血管疾病发展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.