Leptin-based intervention in systemic autoimmunity

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，在免疫反应中也有重要作用。瘦素促进炎症，加速包括系统性红斑狼疮(SLE)在内的多种自身免疫性疾病的发生和发展。因此，我们将在SLE小鼠模型(NZB X NZW)F1(NZB/W F1)小鼠身上测试基于瘦素的干预是否对SLE的病程有利。由于我们假设Leptin影响某些免疫细胞亚群的表型和功能，并干扰/促进可溶性介质的释放，从而在SLE中发挥其致病作用，因此我们将剖析Leptin在NZB/W F1小鼠中诱导的几个细胞和分子事件。我们将研究瘦素对自身反应性T细胞的影响，并将描述一些由瘦素诱导的细胞内信号事件。然后，我们将在这些小鼠身上测试不同的基于瘦素的干预方法，最终为人类的翻译研究奠定基础。通过定义在NZB/W F1小鼠系统自身免疫发展中与瘦素的生理病理学相关的一些关键方面，这些研究将探索狼疮小鼠治疗干预的新策略，用于未来旨在改善这种不治之症管理的人类转化性研究。

DESCRIPTION (provided by applicant): Leptin is a hormone primarily involved in the regulation of basal metabolism that also has an important role in immune responses. Leptin promotes inflammation and can accelerate onset and progression of several autoimmune diseases including systemic lupus erythematosus (SLE). Because of that, we will test whether leptin-based intervention may be beneficial for the course of SLE in a mouse model of SLE, the (NZB x NZW)F1 (NZB/W F1) mouse. Since we hypothesize that leptin affects the phenotype and function of some immune-cell subsets and intereferes/promotes the release of soluble mediators in order to exert its propathogenic effects in SLE, we will dissect several cellular and molecular events induced by leptin in NZB/W F1 mice. We will study the effects of leptin on autoreactive T cells and will characterize some intracellular signaling events induced by leptin. We will then test different approaches of leptin-based intervention in these mice to ultimately set the stage for translational studies to humans. By defining some crucial aspects related to the physiopathology of leptin in the development of systemic autoimmunity in NZB/W F1 mice, these studies will explore new strategies of therapeutic intervention in lupus mice for future translational research in humans aimed at improving management of this incurable disease.