Molecular mechanisms of the impact of Fli-1 on lupus

描述（由申请人提供）： 系统性红斑狼疮（Systemic lupus erythematosus，SLE）是一种以关节炎、血管炎、免疫复合物肾炎和炎症细胞浸润为特征的典型自身免疫性疾病。SLE的发病机制尚未完全明了，虽然已经取得了很大的进展。肾脏疾病是发病率和死亡率的主要原因。先前的研究表明，转录因子Fli-1的过表达在狼疮鼠模型和可能在人类SLE中的疾病发展中起重要作用。Fli-1在正常小鼠中的两到三倍转基因过表达导致狼疮样疾病的发展。活动期狼疮患者外周血淋巴细胞Fli-1 mRNA表达水平高于正常对照组。我们已经发现，在MRL/lpr小鼠和NZM 2410小鼠（小鼠狼疮模型）中，Fli-1表达的遗传减少显著延长了存活期，减少了自身抗体产生，并减少了肾脏病理性增殖变化。基于我们的初步数据，我们的假设是Fli-1在狼疮性肾小球肾炎的进展中在肾脏中的炎性细胞因子和趋化因子的产生以及Toll样受体（TLR）的激活中起关键作用。我们建议在这里进一步定义Fli-1对狼疮疾病发展的影响的分子机制。为解决这一假设，提出了以下具体目标：目标1。确定Fli-1在肾脏疾病发展过程中趋化因子驱动的白细胞募集和激活中的作用。目标二。明确Fli-1在TLR途径及肾损伤中的作用。目标3：确定Fli-1影响肾小球肾炎的分子机制。这些关于Fli-1对小鼠狼疮影响的新研究可能会发现适用于人类狼疮的疾病发病机制的新途径，并有望开发新的治疗药物。 公共卫生相关性： SLE是一种慢性炎症性疾病，被认为是典型的自身免疫性疾病。肾脏疾病是SLE发病和死亡的主要原因。我们的初步数据提供了明确的证据，Fli-1的表达在小鼠SLE中起着关键作用。最引人注目的发现是当Fli-1表达降低时对死亡率的影响。因此，Fli-1对导致MRL/lpr小鼠和NZM 2410小鼠死亡的关键因素沿着减少肾脏疾病具有深远的影响。已经有发表的证据表明Fli-1在人类狼疮中的作用。这个项目是新颖的，因为通过研究Fli-1的作用，我们相信我们将发现以前未被重视的终末器官损伤和小鼠狼疮死亡率的关键途径。这一建议将导致更好地了解疾病发展的机制，并可能提供新的战略治疗疾病。

DESCRIPTION (provided by applicant): Molecular mechanisms of the impact of Fli-1 on lupus Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by arthritis, vasculitis, immune complex glomerulonephritis and infiltration of inflammation cells into the glomeruli. Pathogenesis of SLE is not fully understood although much progress has been made. Renal disease is the major cause of morbidity and mortality. Previous studies indicate that overexpression of transcriptional factor Fli-1 plays an important role in disease development in murine models of lupus and likely in human SLE. Two to three-fold transgenic overexpression of Fli-1 in normal mice results in the development of a lupus-like disease. Active lupus patients have higher Fli-1 mRNA in peripheral lymphocytes compared with normal controls. We have found that genetic reduction of Fli-1 expression in both MRL/lpr mice and NZM2410 mice, murine lupus models, significantly prolonged survival, decreased autoantibody production, and decreased renal pathologic proliferative changes. Our hypothesis based on our preliminary data is that Fli-1 play a critical role in inflammatory cytokine and chemokine production in kidney and activation of Toll-like receptors (TLRs) in the progression of lupus glomerulonephritis. We propose here to further defining the molecular mechanisms of the impact of Fli-1 on lupus disease development. The following specific aims are proposed to address this hypothesis: Aim 1. Determine the role of Fli-1 in chemokine-driven leukocyte recruitment and activation during renal disease development. Aim 2. Define the role of Fli-1 in TLR path way and kidney injury. Aim 3. Determine the molecular mechanism whereby Fli-1 affects glomerulonephritis. These novel studies of the impact of Fli-1 on murine lupus will likely identify new pathways of disease pathogenesis applicable to human lupus and hold promise for the development of new therapeutic agents. PUBLIC HEALTH RELEVANCE: SLE is a chronic inflammatory disease and is considered the prototypic autoimmune disease. Renal disease is the major cause of morbidity and mortality in SLE. Our preliminary data provide clear evidence that Fli-1 expression plays a key role in murine SLE. The most striking finding is the effect on mortality when Fli-1 expression is reduced. Thus, Fli-1 has a profound effect on key factors that lead to mortality in MRL/lpr mice and NZM2410 mice along with reduced renal disease. There is already published evidence suggesting a role for Fli-1 in human lupus. This project is novel in that by studying Fli-1 effects, we believe we will discover previously unappreciated key pathways for end- organ damage and mortality in murine lupus. This proposal will lead to a better understanding of the mechanisms of disease development and perhaps provide novel strategies for the treatment of disease.