The role of leptin in autoimmune-associated hypertension

瘦素在自身免疫相关性高血压中的作用

• 批准号: 10403636
• 负责人: Erin Bassford Taylor
• 金额: $ 25.68万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403636
• 关键词: Adaptive Immune System; Adipose tissue; Animal Model; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cardiovascular Diseases; Cell Survival; Cells; Chronic; Desire for food; Development; Energy Metabolism; Exhibits; Female; Functional disorder; Goals; Hypertension; Hypothalamic structure; Immune System Diseases; Immune Tolerance; Immune system; Inflammation; Injury to Kidney; Leptin; Maintenance; Mediating; Metabolic Diseases; Modeling; Mus; Neuraxis; Pathogenesis; Patients; Peripheral; Plasma; Play; Production; Research; Role; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Work; adipokines; autoimmune pathogenesis; autoreactivity; clinically relevant; cytokine; immune system function

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by a loss of immunological tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. The immune system dysfunction in SLE leads to downstream chronic inflammation and high rates of hypertension, renal injury, and cardiovascular disease. Patients with SLE also have alterations in circulating cytokines, including elevated plasma levels of the adipokine leptin. Leptin is produced by white adipose tissue and has a prominent role in regulating appetite and energy expenditure via its actions in the hypothalamus. However, it also plays a key role in the maintenance and development of inflammation, in part through its direct effects on cells of both the innate and adaptive immune systems. The central goal of this project is to examine the contribution of leptin mediated immune system activation on the pathogenesis of hypertension in SLE. To accomplish this goal, a clinically relevant model of SLE, the female NZBWF1 mouse, will be utilized. Similar to patients with SLE, the NZBWF1 mouse exhibits hypertension, renal injury, and elevated circulating leptin levels, in addition to prominent immune system dysfunction. Work in animal models of autoimmunity strongly implicate leptin in the pathogenesis of autoimmune disease, but the contribution of leptin to the prevalent hypertension during SLE, and the mechanism by which this occurs is unknown. Thus, specific aim 1 will test the hypothesis that elevated leptin during SLE promotes hypertension by stimulating the expansion of proinflammatory TH1 and TH17 cells and decreasing TREG cells. Specific aim 2 will test the hypothesis that elevated leptin during SLE leads to the development of hypertension by promoting B cell survival and the production of autoantibodies. To accomplish these aims, we will administer leptin or block leptin signaling, and test the impact on the development of B and T lymphocyte dysfunction and autoimmune-associated hypertension. Because leptin acts both centrally (central nervous system) and peripherally, we will also examine relative contribution of central and peripheral leptin on immune system function.

系统性红斑狼疮(SLE)是一种多系统自身免疫性疾病，其特征是 免疫耐受和自身反应性T和B淋巴细胞的扩张，导致 产生自身抗体。系统性红斑狼疮免疫系统功能障碍导致下游慢性 炎症和高血压、肾脏损伤和心血管疾病的高发生率。系统性红斑狼疮患者 循环中的细胞因子也有变化，包括血浆脂肪因子瘦素水平升高。 瘦素是由白色脂肪组织产生的，在调节食欲和能量方面具有突出作用。 通过它在下丘脑的活动而产生的支出。然而，它在维护和维护方面也发挥着关键作用 炎症的发展，部分是通过它对先天细胞和获得性细胞的直接影响 免疫系统。这个项目的中心目标是检查瘦素介导的贡献 免疫系统激活在系统性红斑狼疮高血压发病中的作用为了实现这一目标，一个 临床相关的系统性红斑狼疮模型雌性NZBWF1小鼠将被利用。与系统性红斑狼疮患者相似， NZBWF1小鼠表现出高血压、肾脏损伤和循环瘦素水平升高，此外 严重的免疫系统功能障碍。自身免疫动物模型的研究与瘦素密切相关 在自身免疫性疾病的发病机制中，瘦素在高血压流行中的作用 在系统性红斑狼疮期间，这种情况发生的机制尚不清楚。因此，特定目标1将测试 SLE期间瘦素升高通过刺激血管扩张促进高血压的假说 促炎症的TH1、TH17细胞和减少的Treg细胞。《特定目标2》将检验这一假设 SLE期间瘦素的升高通过促进B细胞的存活和 自身抗体的产生。为了达到这些目的，我们将给予瘦素或阻断瘦素。 信号，并测试对B和T淋巴细胞功能障碍和发展的影响 自身免疫性高血压。因为瘦素既起中枢作用(中枢神经系统)又起作用 在外围，我们还将检查中枢和外周瘦素对免疫系统的相对贡献 功能。