The Impact of Obesity and Leptin on the Development of Immune System Dysfunction and Hypertension in Females with Systemic Lupus Erythematous

肥胖和瘦素对女性系统性红斑狼疮免疫系统功能障碍和高血压的影响

• 批准号: 10714532
• 负责人: Erin Bassford Taylor
• 金额: $ 31.54万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714532
• 关键词: Adipose tissue; Adrenergic Receptor; Affect; American; Appetite Regulation; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Awareness; B-Lymphocytes; Blood Pressure; Body mass index; Bone Marrow; Brain; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Central obesity; Chronic; Clinical Data; Control Animal; Data; Deposition; Development; Diet; Disease; Disease Progression; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Female; Flow Cytometry; Functional disorder; Goals; Hematopoietic; High Fat Diet; Homeostasis; Hypertension; Hypothalamic structure; Immune; Immune System Diseases; Immune system; Immunoglobulin G; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Intervention; Kidney; Knowledge; Laboratories; Lead; Leptin; LoxP-flanked allele; Lupus; Mediating; Modeling; Morbidity - disease rate; Mus; Normal Range; Obesity; Operative Surgical Procedures; Overweight; Pathogenesis; Pathogenicity; Patients; Peripheral; Population; Pristane; Production; Publishing; Risk; Role; Rural; Self Tolerance; Signal Pathway; Signal Transduction; Sympathetic Nervous System; Systemic Lupus Erythematosus; T cell infiltration; T-Lymphocyte; Techniques; Testing; Tissues; Visceral; Woman; adipokines; antagonist; anti-dsDNA autoantibody; autoreactive B cell; autoreactivity; clinically relevant; comparison control; eosinophil; hypertensive; immune function; improved; in vivo; insight; leptin receptor; mortality; nestin protein; patient population; pharmacologic; treatment effect

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that primarily affects women and is characterized by a loss of self-tolerance and expansion of autoreactive B and T lymphocytes, leading to the production of autoantibodies. The autoantibody production leads to chronic inflammation, resulting in high rates of hypertension and cardiovascular disease. Clinical data indicate that rates of obesity are increased in patients with SLE, and even in the absence of an overweight or obese BMI, patients with SLE have altered fat deposition and increased visceral adiposity compared to BMI-matched controls. SLE patients also have elevated circulating levels of the adipokine leptin, including those patients with a BMI in the normal range. The central goal of this project is to examine the pathogenic role of obesity and leptin in the development and progression of SLE disease and the development of hypertension. To accomplish this goal, two clinically relevant models of SLE, the female NZBWF1 mouse and the pristane-inducible model, will be utilized. Both models develop hypertension as the disease progresses, and the NZBWF1 mouse exhibits obesity and hyperleptinemia on a normal chow diet. In aim 1 we will use the NZBWF1 mouse to test the hypothesis that increased visceral adiposity in SLE exacerbates disease progression and the development of hypertension via pathogenic immune cells in adipose tissue. We will use surgical and pharmacological techniques to deplete adipose tissue or specific immune cell populations within the adipose, and then assess the effect of these treatments on SLE disease progression and the development of hypertension. Published and preliminary data indicate that leptin has effects on the immune system via both direct effects on immune cells, and indirectly via signaling in the brain. To assess the role of leptin in SLE disease progression by directly affecting immune cells, aim 2 will utilize the pristane- inducible model of SLE and test the hypothesis that elevated leptin during SLE promotes disease progression via direct effects on B and T lymphocytes in peripheral tissues. We will generate mice that lack leptin receptors on B or T lymphocytes and induce SLE using pristane. In aim 3, we will test the hypothesis that leptin promotes SLE disease via its actions in the CNS. First, we will induce lupus using pristane in mice that lack leptin receptors in the CNS (Nestin-Cre x LepRflox/flox). We will also test whether the effects of leptin on autoimmune disease progression are mediated by the sympathetic nervous system by utilizing adrenergic receptor blockade. Together, the proposed studies will provide insight into distinct mechanisms whereby obesity and adipokine dysregulation lead to immune system dysfunction and the development of hypertension in SLE.

项目总结/摘要 系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，主要影响女性， 其特征在于自身耐受性的丧失和自身反应性B和T淋巴细胞的扩增，导致 自身抗体的产生。自身抗体的产生会导致慢性炎症， 高血压和心血管疾病。临床数据表明，肥胖症患者的发病率增加， 即使没有超重或肥胖的BMI，SLE患者的脂肪沉积也发生了改变。 与BMI匹配的对照组相比，内脏肥胖增加。SLE患者还具有升高的循环 脂肪因子瘦素水平，包括BMI在正常范围内的患者。这个项目的中心目标是 该项目旨在研究肥胖和瘦素在肥胖发生和发展中的致病作用， SLE疾病与高血压的发展。为了实现这一目标，两个临床相关模型 将使用SLE的雌性NZBWF 1小鼠和降植烷诱导模型。两种模式都发展 随着疾病的进展，NZBWF 1小鼠表现出肥胖和高瘦素血症， 正常饮食在目的1中，我们将使用NZBWF 1小鼠来测试增加内脏免疫的假设。 SLE中的肥胖通过致病性免疫反应加剧疾病进展和高血压的发展 脂肪组织中的细胞。我们将使用手术和药理学技术来消耗脂肪组织或特定的 脂肪内的免疫细胞群，然后评估这些治疗对SLE疾病的影响 进展和高血压的发展。已发表的和初步的数据表明， 通过对免疫细胞的直接影响和通过大脑中的信号间接影响免疫系统。评估 瘦素在SLE疾病进展中的作用是通过直接影响免疫细胞，目的2将利用降植烷- SLE诱导模型，并检验SLE期间瘦素升高促进疾病进展的假设 通过直接作用于外周组织中的B和T淋巴细胞。我们将培育出缺乏瘦素受体的小鼠 对B或T淋巴细胞的作用，并使用降植烷诱导SLE。在目标3中，我们将检验瘦素促进 SLE疾病通过其在CNS中的作用。首先，我们将使用降植烷在缺乏瘦素受体的小鼠中诱导狼疮 Nestin-Cre x LepRflox/flox。我们还将测试瘦素对自身免疫性疾病的影响是否 进展是由交感神经系统通过利用肾上腺素能受体阻断来介导的。 总之，拟议的研究将提供深入了解不同的机制， SLE患者的免疫功能失调导致免疫系统功能障碍和高血压的发生。