The role of CSF-1 in the pathogenesis of lupus nephritis

描述（由申请人提供）：肾炎是人类自身免疫性疾病系统性红斑狼疮（SLE）的常见并发症。MRL-Faslpr菌株的小鼠会自发地发展成一种类似SLE的疾病。研究表明，MRL-Faslpr毒株中巨噬细胞（MO）在狼疮性肾炎中表现突出，并且在炎症过程中，巨噬细胞被激活后破坏肾常驻细胞。集落刺激因子-1 （CSF-1）是MRL-Faslpr小鼠狼疮性肾炎的主要生长因子。CSF-1的作用完全由CSF-1受体（csf - 1r）介导。有三种单独的CSF-1亚型，细胞表面CSF-1 (csCSF)，分泌蛋白聚糖（spCSF）和分泌糖蛋白（sgCSF）。我们假设CSF-1和csf - 1r承载细胞在狼疮性肾炎的发病机制中起核心作用。为了验证这一假设，我们提出：1)确定过表达CSF-1是否系统性地加速了MRL-Faslpr小鼠狼疮肾炎和全身性疾病的发生；2)确定单个CSF-1亚型在MRL-Faslpr小鼠狼疮肾炎和全身性疾病中的作用；3)确定MRL-Faslpr小鼠疾病期间消除CSF-1信号是否可以阻止狼疮肾炎和全身性疾病的进展。这些目标将使我们能够评估阻断/消除CSF-1介导的信号在治疗狼疮性肾炎和其他巨噬细胞介导的疾病中的潜在治疗价值。肾脏炎症是狼疮患者发病和死亡的主要原因。这种炎症在很大程度上是由被称为巨噬细胞的白细胞亚群介导的，巨噬细胞破坏肾脏内的组织。研究表明，主要的巨噬细胞生长因子CSF-1可促进自发发展为与人类狼疮具有许多特征的疾病的小鼠的肾脏炎症。我们将使用这些小鼠来确定CSF-1依赖性炎症的具体机制，并确定CSF-1途径是否是狼疮和其他巨噬细胞介导的人类肾脏疾病的潜在治疗靶点。

DESCRIPTION (provided by applicant): Nephritis is a common complication of the human autoimmune disease systemic lupus erythematosus (SLE). Mice of the MRL-Faslpr strain spontaneously develop a disease that is similar to SLE. It has been shown that macrophages (MO) are prominent in lupus nephritis in the MRL-Faslpr strain and that upon activation, MO destroy renal resident cells during inflammation. Colony Stimulating Factor-1 (CSF-1), the principal MO growth factor, is required to promote lupus nephritis in MRL-Faslpr mice. The actions of CSF-1 are mediated exclusively by the CSF-1 receptor (CSF-1 R). There are three individual CSF-1 isoforms, a cell surface CSF-1 (csCSF), a secreted proteoglycan (spCSF) and a secreted glycoprotein (sgCSF). We hypothesize that CSF-1 and CSF-1 R bearing cells are central in the pathogenesis of lupus nephritis. In order to test this hypothesis, we propose: 1) to determine whether over-expressing CSF-1 systemically accelerates lupus nephritis and the systemic illness in MRL-Faslpr mice; 2) to determine the role(s) of the individual CSF-1 isoforms in lupus nephritis and systemic illness in MRL-Faslpr mice; and 3) to determine whether eliminating CSF-1 signaling during disease in MRL-Faslpr mice can halt the progression of lupus nephritis and the systemic illness. These aims will allow us to evaluate the potential therapeutic value of blocking/eliminating CSF-1 mediated signals in the treatment of lupus nephritis and other macrophage-mediated illnesses. Kidney inflammation is a major cause of morbidity and mortality in lupus patients. This inflammation is mediated in large part by a subset of white blood cells known as macrophages that destroy tissue within the kidney. It has been shown that CSF-1, the principle macrophage growth factor, promotes kidney inflammation in mice that spontaneously develop a disease that shares many of the characteristics of human lupus. We will use these mice to determine the specific mechanisms of CSF-1 dependent inflammation and establish whether the CSF-1 pathway is a potential therapeutic target for lupus and other macrophage-mediated kidney diseases in humans..