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，其特征是失去 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 中的免疫系统功能障碍导致下游慢性病 炎症以及高血压、肾损伤和心血管疾病的高发病率。系统性红斑狼疮患者 循环细胞因子也发生改变，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作用 通过其在下丘脑的作用进行支出。但它在维护和保养方面也发挥着关键作用。 炎症的发展，部分是通过其对先天性和适应性细胞的直接影响 免疫系统。该项目的中心目标是检查瘦素介导的贡献 免疫系统激活对 SLE 高血压发病机制的影响。为了实现这一目标，一个 将使用 SLE 的临床相关模型，即雌性 NZBWF1 小鼠。与 SLE 患者类似， 此外，NZBWF1 小鼠表现出高血压、肾损伤和循环瘦素水平升高 导致显着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，但瘦素对流行高血压的贡献 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 假设 SLE 期间瘦素升高通过刺激 促炎性 TH1 和 TH17 细胞以及减少性 TREG 细胞。具体目标 2 将检验假设 SLE 期间瘦素升高可促进 B 细胞存活并导致高血压的发生 自身抗体的产生。为了实现这些目标，我们将施用瘦素或阻断瘦素 信号传导，并测试对 B 和 T 淋巴细胞功能障碍发展的影响以及 自身免疫相关的高血压。因为瘦素具有中枢（中枢神经系统）和 在外周方面，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。