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.

项目摘要/摘要 全身性红斑狼疮（SLE）是一种慢性自身免疫性疾病，主要影响女性和 其特征是自耐丧失和自动反应性B和T淋巴细胞的扩张，导致 产生自身抗体。自身抗体产生导致慢性炎症，导致高率 高血压和心血管疾病。临床数据表明患者的肥胖率有所提高 使用SLE，甚至在没有超重或肥胖的BMI的情况下，SLE的患者脂肪沉积改变了 与BMI匹配的对照相比，内脏肥胖增加了。 SLE患者的循环也升高 脂肪因子瘦素的水平，包括正常范围内BMI的患者。这个中心目标 项目是检查肥胖和瘦素在发育和发展中的致病作用 SLE病和高血压的发展。为了实现这一目标，两个与临床相关的模型 将利用雌性NZBWF1小鼠和Pristane诱导模型的SLE。两种模型都会发展 随着疾病的进展，高血压，NZBWF1小鼠在A上表现出肥胖和高血治血症 普通食物饮食。在AIM 1中，我们将使用NZBWF1小鼠来测试增加内脏的假设 SLE的肥胖加剧了疾病的进展和通过致病性免疫的高血压发展 脂肪组织中的细胞。我们将使用手术和药理技术来耗尽脂肪组织或特定 脂肪中的免疫细胞群体，然后评估这些治疗对SLE病的影响 进展和高血压的发展。已发布并初步数据表明瘦素具有影响 在免疫系统上通过对免疫细胞的直接影响，并通过大脑中的信号间接影响。评估 通过直接影响免疫细胞，瘦素在SLE疾病进展中的作用，AIM 2将利用Pristane- SLE的诱导模型和检验的假设，即SLE期间瘦素升高可促进疾病进展 通过对周围组织中B和T淋巴细胞的直接作用。我们将产生缺乏瘦素受体的小鼠 在B或T淋巴细胞上，并使用Pristane诱导SLE。在AIM 3中，我们将测试瘦素促进的假设 通过在中枢神经系统中的作用而进行的SLE病。首先，我们将在缺乏瘦素受体的小鼠中使用pristane诱导狼疮 在CNS（Nestin-Cre X Leprflox/Flox）中。我们还将测试瘦素对自身免疫性疾病的影响 进展是通过使用肾上腺素能受体阻滞来介导的。 拟议的研究将共同​​洞悉肥胖和脂肪因子的不同机制 失调导致免疫系统功能障碍和SLE中高血压的发展。