Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma

项目总结 创伤后应激障碍(PTSD)是一种使人衰弱的心理状况，它增加了 威胁生命的炎症性疾病，如高血压，超过50%。这个项目的目标是 特别关注调节心理创伤所致心理创伤的神经T淋巴细胞机制 炎症和高血压的易感性。我们实验室使用临床前试验的先前结果 被称为反复社会失败应激(RSD)的创伤后应激障碍模型显示，脾T淋巴细胞 心理创伤后炎症的主要来源。此外，我们还鉴定了RSD-小鼠 表现出对血管紧张素II(AngII)的高血压反应，血管紧张素II模拟心血管 在创伤后应激障碍患者中观察到疾病敏感化。重要的是，缺乏T淋巴细胞的小鼠没有致敏 对Angii来说，这意味着T淋巴细胞驱动的炎症是一种机制上的血压调节 RSD。此外，我们还阐明了T细胞产生促炎细胞因子之间的密切联系。 淋巴细胞、交感神经系统激活、线粒体氧化还原环境(主要是 在T淋巴细胞中，焦虑样行为，以及血压敏感度的发展 这表明这些生理因素是机械地相互交织在一起的。鉴于这一信息，我们 将检验以下中心假说：RSD后交感神经兴奋增加驱动脾T- 淋巴细胞炎症通过增加线粒体超氧化物来增强对 高血压。我们的特定目标将决定神经免疫途径和细胞内机制 控制创伤后应激障碍RSD模型的T淋巴细胞炎症。这项建议的创新之处在于 中枢和局部自主控制T淋巴细胞调节血压敏化的概念 线粒体超氧化物歧化调控心理后T淋巴细胞炎症的生物学鉴定 创伤，以及我们新的基因工程动物模型和 神经调节技术。总体而言，该项目将揭示T淋巴细胞炎症在 心理创伤，并旨在利用这一证据，通过早期的创伤后应激障碍的临床治疗 心血管筛查或有针对性的治疗干预。

PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a debilitating psychological condition that increases the risk of life-threatening comorbid inflammatory diseases such as hypertension by over 50%. The goal of this project is to focus specifically on the neurological-T-lymphocyte mechanisms that regulate psychological trauma-induced inflammation and the predisposition to hypertension. Previous results from our laboratory using a preclinical model of PTSD known as repeated social defeat stress (RSDS) have demonstrated splenic T-lymphocytes as a primary source of inflammation after psychological trauma. Furthermore, we identified that RSDS-mice display a heightened blood pressure response to angiotensin II (AngII), which mimics the cardiovascular disease sensitization observed in PTSD patients. Importantly, mice lacking T-lymphocytes were not sensitized to AngII, which implies T-lymphocyte-driven inflammation as a mechanistic regulator of blood pressure after RSDS. We have additionally elucidated tight links between pro-inflammatory cytokine production from T- lymphocytes, sympathetic nervous system activation, the mitochondrial redox environment (primarily superoxide) in T-lymphocytes, anxiety-like behavior, and the development of a blood pressure sensitization to AngII, which suggests these physiological elements are mechanistically-intertwined. Given this information, we will test the central hypothesis that increased sympathoexcitation after RSDS drives splenic T- lymphocyte inflammation through increased mitochondrial superoxide to enhance sensitivity to hypertension. Our Specific Aims will determine neuroimmune pathways and intracellular mechanisms that control T-lymphocyte inflammation in the RSDS model of PTSD. The innovation in this proposal lies in the concept of central and local autonomic control of T-lymphocytes regulating blood pressure sensitization, the biological identification of mitochondrial superoxide regulating T-lymphocyte inflammation after psychological trauma, and the technological advances of our new genetically-engineered animal models and neuromodulation techniques. Overall, this project will reveal the impact of T-lymphocyte inflammation after psychological trauma, and aims to utilize this evidence to inform clinical management of PTSD via earlier cardiovascular screening or targeted therapeutic intervention.