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: 10629301
• 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/10629301
• 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; IL17 gene; Immune System Diseases; Incidence; Inflammation; Inflammatory; Interleukin-10; Interleukin-2; Intervention; Knockout Mice; Laboratories; 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; Technology; 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 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）是一种使人衰弱的心理状况， 威胁生命的共病炎症性疾病，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诱导的神经T淋巴细胞机制， 炎症和易患高血压。我们实验室使用临床前 被称为反复社交失败压力（RSDS）的PTSD模型已经证明脾脏T淋巴细胞是 心理创伤后炎症的主要来源此外，我们发现， 显示对血管紧张素II（AngII）的高血压反应，这模拟了心血管疾病。 在PTSD患者中观察到的疾病敏感性。重要的是，缺乏T淋巴细胞的小鼠不会被致敏。 血管紧张素II，这意味着T淋巴细胞驱动的炎症作为一种机械调节血压后， RSDS。我们还阐明了T细胞的促炎细胞因子产生与T细胞的促炎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）的T淋巴细胞，焦虑样行为，并发展的血压敏感性， AngII，这表明这些生理因素是机械交织在一起的。根据这些信息，我们 将检验中心假设，即RSDS后增加的交感兴奋驱动脾T细胞， 淋巴细胞炎症通过增加线粒体超氧化物来增强对 高血压我们的具体目标将确定神经免疫途径和细胞内机制， 对照PTSD的RSDS模型中的T淋巴细胞炎症。本提案的创新之处在于， 概念的中枢和局部自主控制的T淋巴细胞调节血压敏化， 线粒体超氧化物调节T淋巴细胞炎症的生物学鉴定 创伤，以及我们新的基因工程动物模型的技术进步， 神经调节技术总的来说，这个项目将揭示T淋巴细胞炎症的影响后， 心理创伤，并旨在利用这一证据，通知临床管理创伤后应激障碍，通过早期 心血管筛查或靶向治疗干预。

项目成果

Cytokine levels throughout the perinatal period.

• DOI: 10.1080/14767058.2021.1887121
• 发表时间: 2022-12
• 期刊: The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
• 作者: Moore TA;Case AJ
• 通讯作者: Case AJ

Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen.

• DOI: 10.1016/j.bbih.2023.100690
• 发表时间: 2023-12
• 期刊: Brain, behavior, & immunity - health

Defining the nuanced nature of redox biology in post-traumatic stress disorder.

• DOI: 10.3389/fphys.2023.1130861
• 发表时间: 2023
• 期刊: Frontiers in physiology
• 影响因子: 4

Elevated CRP and TNF-α levels are associated with blunted neural oscillations serving fluid intelligence.

CRP 和 TNF-α 水平升高与流体智力的神经振荡减弱有关。

• DOI: 10.1016/j.bbi.2023.09.012
• 发表时间: 2023
• 期刊: Brain, behavior, and immunity
• 作者: Dietz,SarahM;Schantell,Mikki;Spooner,RachelK;Sandal,MeganE;Mansouri,Amirsalar;Arif,Yasra;Okelberry,HannahJ;John,JasonA;Glesinger,Ryan;May,PamelaE;Heinrichs-Graham,Elizabeth;Case,AdamJ;Zimmerman,MatthewC;Wilson,TonyW
• 通讯作者: Wilson,TonyW