Role of Leptin in Systemic Lupus Erythematosus

描述（由申请人提供）：瘦素是一种主要参与调节基础代谢的激素，在免疫反应中起重要作用。瘦素促进炎症，并能加速小鼠几种自身免疫性疾病的发生和发展。我们有初步的数据表明，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，并将测试基于瘦素干预SLE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中的促致病作用，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（细胞信号传导）。然后，我们将使用不同的瘦素拮抗剂测试基于瘦素的SLE治疗干预的不同方法，首先在体外，然后在体内，最终为人类的翻译研究奠定基础。同时，我们将进行遗传关联研究，以确定SLE中瘦素相关多态性是否可以通过调节瘦素水平或对瘦素的反应性来促成易感背景。通过定义与瘦素在SLE中的生理病理相关的一些关键方面，这些研究将探索SLE治疗干预的新策略，最终可能导致疾病管理的改善。项目描述：瘦素是一种控制人体多种功能的激素，包括免疫反应。我们有初步的数据表明，瘦素在系统性红斑狼疮的发生和发展中发挥重要作用。红斑狼疮是一种不治之症，其特点是全身效应，并产生针对自身成分的抗体，导致不可逆的肾脏损害。本研究将详细介绍瘦素对人类狼疮的影响，并比较不同的基于瘦素的方法的潜力，以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.