Role of Leptin in Systemic Lupus Erythematosus

描述(申请人提供)：瘦素是一种激素，主要参与基础代谢的调节，并在免疫反应中发挥重要作用。瘦素促进炎症，并可加速小鼠多种自身免疫性疾病的发生和发展。我们有初步数据表明，瘦素也可能在小鼠和人类系统性红斑狼疮(SLE)的发病机制中发挥作用。正因为如此，我们将剖析瘦素对人类SLE的免疫作用，并将测试基于瘦素的SLE干预的新可能性。由于我们假设瘦素影响免疫细胞亚群的表型和功能，并促进可溶性介质的释放，以发挥其在SLE中的致病作用，因此我们将研究瘦素在人类SLE中诱导的几个细胞方面(表型、功能)和分子事件(细胞信号)。然后，我们将使用不同的瘦素拮抗剂，首先在体外，然后在体内测试基于瘦素的治疗干预SLE的不同方法，最终为人类翻译研究奠定基础。同时，我们将进行遗传关联研究，以确定SLE中与瘦素相关的基因多态是否通过调节瘦素水平或对瘦素的反应而导致易感背景。通过定义与SLE中瘦素的生理病理相关的一些关键方面，这些研究将探索治疗SLE的新策略，最终可能导致改善对疾病的管理。对该项目的简单描述：瘦素是一种荷尔蒙，它控制着人类的几项功能，包括免疫反应。我们有初步数据表明，瘦素可以在系统性红斑狼疮的发生和发展中发挥重要作用，系统性红斑狼疮是一种不治之症，其特征是全身影响和自身成分产生抗体，导致不可逆转的肾脏损害。这项研究将详细说明瘦素对人类狼疮的影响，并比较不同基于瘦素的方法的潜力，目的是改善目前人类狼疮的治疗管理。

DESCRIPTION (provided by applicant): Leptin is a hormone primarily involved in the regulation of basal metabolism and with an important role in immune responses. Leptin promotes inflammation and can accelerate onset and progression of several autoimmune diseases in mice. We have preliminary data that suggest that leptin may also play a role in the pathogenesis of murine and human systemic lupus erythematosus (SLE). Because of that, we will dissect the immune effects of leptin on human SLE and will test new possibilities of leptin-based intervention in SLE. Since we hypothesize that leptin affects the phenotype and function of immune-cell subsets and promotes the release of soluble mediators in order to exert its pro-pathogenic effects in SLE, we will study several cellular aspects (phenotype, function) and molecular events (cell signaling) induced by leptin in human SLE. We will then test different approaches of leptin-based therapeutic intervention in SLE using different leptin antagonists, first in vitro and then in vivo, to ultimately set the stage for translation studies to humans. In parallel, we will do genetic association studies to address whether leptin-related polymorphisms in SLE can contribute to a predisposing background by modulating leptin levels or responsiveness to leptin. By defining some crucial aspects related to the physiopathology of leptin in SLE, these studies will explore new strategies of therapeutic intervention for SLE that may ultimately lead to improved management of the disease. LAY DESCRIPTION OF THE PROJECT: Leptin is a hormone that controls several functions in humans, including immune responses. We have preliminary data that suggest that leptin can play an important role in the development and progression of systemic lupus erhytematosus, an incurable disease that is characterized by systemic effects and by the production of antibodies to self components that cause irreversible kidney damage. This study will detail the effects of leptin on human lupus and compare the potential of different leptin-based approaches with the goal to improve the current therapeutic management of human lupus.