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: 10159926
• 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/10159926
• 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淋巴细胞的扩增，导致 自身抗体的产生。SLE患者的免疫系统功能障碍导致下游慢性炎症反应。 炎症和高血压、肾损伤和心血管疾病的高发病率。SLE患者 也有循环细胞因子的改变，包括脂肪因子瘦素的血浆水平升高。 瘦素由白色脂肪组织产生，在调节食欲和能量方面具有突出的作用 通过其在下丘脑中的作用来消耗。然而，它也在维护和 炎症的发展，部分是通过其对先天和适应性细胞的直接影响， 免疫系统该项目的中心目标是研究瘦素介导的 免疫系统激活在SLE高血压发病机制中的作用为了实现这一目标， 将使用SLE的临床相关模型，雌性NZBWF 1小鼠。与SLE患者相似， NZBWF 1小鼠表现出高血压、肾损伤和升高的循环瘦素水平，此外 导致免疫系统功能失调。在自身免疫动物模型中的工作强烈暗示瘦素 在自身免疫性疾病的发病机制中， 在SLE期间，这种情况发生的机制尚不清楚。因此，具体目标1将测试 SLE期间瘦素升高通过刺激血管扩张而促进高血压的假说 促炎性TH1和TH17细胞以及减少的Treg细胞。具体目标2将检验假设 SLE期间瘦素升高通过促进B细胞存活导致高血压的发展， 自身抗体的产生。为了实现这些目标，我们将管理或阻止瘦素 信号传导，并测试对B和T淋巴细胞功能障碍的发展的影响， 自身免疫相关性高血压因为瘦素既作用于中枢（中枢神经系统）， 在外周，我们还将研究中枢和外周瘦素对免疫系统的相对贡献 功能