Neuroimmune contributions to hypertension sensitization in a preclinical model of PTSD

PTSD 临床前模型中神经免疫对高血压敏化的贡献

• 批准号: 10307991
• 负责人: Safwan Kijana Elkhatib
• 金额: $ 4.29万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307991
• 关键词: Address; Affect; American; Angiotensin II; Animals; Automobile Driving; Behavioral; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cells; Characteristics; Chemosensitization; Data; Development; Disease; Enzymes; Etiology; Exposure to; Genetic; Hypertension; Immune; In Vitro; Inflammation; Inflammatory; Interleukin-17; Interleukin-6; Interleukins; Knockout Mice; Knowledge; Link; Longevity; Mediating; Mental disorders; Morbidity - disease rate; Mus; Nerve; Neuroimmune; Neurons; Neurotransmitters; Pathogenesis; Patients; Physiological; Post-Traumatic Stress Disorders; Pre-Clinical Model; Production; Regulation; Reporting; Risk; Role; Signal Transduction; Source; Spleen; Stress; T-Lymphocyte; Therapeutic; Trauma; Tyrosine 3-Monooxygenase; base; behavioral phenotyping; cytokine; design; genetic signature; in vivo; inflammatory milieu; insight; mortality; mouse model; neurotransmission; novel; novel therapeutics; pre-clinical; psychological trauma; response; social; social defeat

PROJECT SUMMARY Post-traumatic stress disorder (PTSD) is a devastating psychiatric disorder that afflicts more than 7% of all Americans across their lifespan. PTSD increases the risk for inflammatory cardiovascular diseases, such as hypertension, but the etiology of this increased predilection for hypertension after trauma is unknown. Both PTSD and hypertension characteristically display increases in circulating levels of catecholamines, as well as alterations in T-lymphocyte-driven inflammation. T-lymphocytes are highly reactive to catecholamines, and we have previously reported that splenic T-lymphocytes exposed to these neurotransmitters in vitro secrete increased levels of interleukin 6 (IL-6) and interleukin 17A (IL-17A); pro-inflammatory cytokines which have been mechanistically linked to the pathogenesis of hypertension. Furthermore, using an accepted preclinical mouse model of PTSD known as repeated social defeat, we have also recently described increased splenic catecholamine levels, elevated circulating IL-6 and IL-17A levels, as well as a potentiated hypertensive response to angiotensin II (AngII) in animals undergoing this psychological trauma. These observations were abrogated in socially-defeated mice lacking T-lymphocytes, demonstrating these adaptive immune cells are mechanistic in the sensitization to hypertension after trauma. To this end, I hypothesize that psychological trauma increases the splenic catecholamine milieu that drives T-lymphocyte inflammation causing hypertension sensitization. In Specific Aim 1, I will determine the contribution of neuronally-derived catecholamines in the sensitization of hypertension by selectively ablating the splenic nerve. In Specific Aim 2, I will utilize a novel genetic knockout mouse model that lacks tyrosine hydroxylase—the rate-limiting enzyme in catecholamine synthesis—exclusively in T- lymphocytes. I will investigate the contribution of these sources of catecholamines to the A) behavioral phenotype, B) T-lymphocyte autonomic and inflammatory profiles, and C) development of hypertension. Completion of these aims will further our ability to design and implement novel therapies that will ultimately reduce the morbidity and mortality of cardiovascular disease in PTSD patients.

项目摘要 创伤后应激障碍（PTSD）是一种毁灭性的精神障碍，苦难比 在他们的一生中，有7％的美国人。 PTSD增加了炎症性心血管的风险 疾病，例如高血压，但是这种高血压预测的病因增加了 创伤是未知的。 PTSD和高血压在循环中都显示出增加 儿茶酚胺的水平以及T淋巴细胞驱动的注射的改变。 对儿茶酚胺具有高反应性，我们以前已经报道了脾淋巴细胞 在体外暴露于这些神经递质的秘密中增加了白介素6（il-6）和 白介素17a（IL-17a）;促炎性细胞因子与 高血压的发病机理。此外，使用PTSD的接受的临床前小鼠模型 被称为反复的社交失败，我们最近还描述了增加的脾脏儿茶酚胺 水平，循环IL-6和IL-17A水平升高，以及对 血管紧张素II（Angii）的动物经历了这种心理创伤。这些观察是 在缺乏T淋巴细胞的社会败心小鼠中一经，证明了这些适应性免疫 细胞在创伤后对高血压的敏感性是机械的。为此，我假设 心理创伤增加了驱动T淋巴细胞的脾脏儿茶酚胺环境 炎症导致高血压致敏。在特定目标1中，我将确定 神经源性的儿茶酚胺在高血压的敏感性中，通过选择性擦洗 脾神经。在特定的目标2中，我将利用缺乏的新型遗传基因敲除鼠标模型 酪氨酸羟化酶（catecholamine合成中的速率限制酶）在T-中固定 淋巴细胞。我将调查这些儿茶酚胺来源对A的贡献） 行为表型，b）t淋巴细胞自主和炎症概况，c）发展 高血压。这些目标的完成将进一步我们设计和实施新颖的能力 最终将降低PTSD中心血管疾病的发病率和死亡率的疗法 患者。