Neuroimmune dynamics involved in the pathogenesis of hypertension after psychological trauma

神经免疫动力学参与心理创伤后高血压的发病机制

• 批准号: 10450810
• 负责人: Adam J Case
• 金额: $ 54.27万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450810
• 关键词: Angiotensin II; Animal Model; Animals; Attenuated; Autocrine Communication; Behavioral; Biological; Biological Markers; Blood Pressure; COVID-19 pandemic; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cells; Chronic; Clinical; Clinical Management; Collection; Communities; Data; Denervation; Development; Disease; Elements; Environment; Enzymes; Event; General Population; Genetic Engineering; Goals; Grant; Hypertension; Immune System Diseases; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Interleukin-2; Intervention; Knockout Mice; Laboratories; Lead; Life; Link; Mental disorders; Messenger RNA; Mitochondria; Modeling; Mus; Neuroimmune; Neurologic; Neurons; Norepinephrine; Operative Surgical Procedures; Organ; Oxidation-Reduction; Paracrine Communication; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptides; Physiological; Post-Traumatic Stress Disorders; Pre-Clinical Model; Predisposition; Production; Public Health; Reactive Oxygen Species; Regulation; Risk; Signal Pathway; Signal Transduction; Source; Spleen; Stress; Superoxides; Sympathetic Nervous System; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic Intervention; Tyrosine 3-Monooxygenase; United States; anxiety-like behavior; blood pressure regulation; comorbidity; cytokine; designer receptors exclusively activated by designer drugs; genetic manipulation; hypertensive; innovation; interleukin-22; mortality; mouse model; neuroregulation; neurotransmission; new therapeutic target; novel; patient population; pre-clinical; prevent; psychologic; psychological trauma; response; screening; social; social defeat; targeted treatment

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.

项目摘要 创伤后应激障碍（PTSD）是一种令人衰弱的心理状况，可增加 威胁生命的合并症炎症性疾病，例如高血压超过50％。这个项目的目标是 专门针对调节心理创伤诱导的神经T-淋巴细胞机制 炎症和高血压的倾向。我们实验室的先前结果使用临床前 PTSD的模型被称为重复的社交失败压力（RSD）已显示出脾脏T淋巴细胞为 心理创伤后的炎症的主要来源。此外，我们确定了RSDS小鼠 表现出对血管紧张素II（ANGII）的血压升高，该反应模仿心血管 PTSD患者观察到疾病敏化。重要的是，缺乏T淋巴细胞的小鼠没有敏感 到Angii，这意味着T淋巴细胞驱动的炎症是作为血压的机械调节剂 RSD。我们还阐明了T-的促炎性细胞因子产生之间的紧密联系 淋巴细胞，交感神经系统激活，线粒体氧化还原环境（主要是 超氧化物）在T淋巴细胞，焦虑症行为以及血压敏化对 Angii，这表明这些生理元素是机械上纠缠的。鉴于此信息，我们 将测试中心假设，即在RSD驱动脾脏T-之后增加交感神经激素 通过增加线粒体超氧化物的淋巴细胞炎症，增强对 高血压。我们的具体目的将确定神经免疫性途径和细胞内机制 PTSD的RSDS模型中的控制T-淋巴细胞炎症。此提案的创新在于 调节血压敏化的T淋巴细胞的中央和局部自主控制的概念 心理学后的线粒体超氧化物调节T-淋巴细胞炎症的生物学鉴定 创伤以及我们新的遗传工程动物模型的技术进步和 神经调节技术。总体而言，该项目将揭示T-淋巴细胞炎症的影响 心理创伤，旨在利用此证据来通知PTSD的临床管理 心血管筛查或有针对性的治疗干预。