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

CSF-1在狼疮性肾炎发病机制中的作用

• 批准号: 7570092
• 负责人: Julie Ann Lucas
• 金额: $ 5.34万
• 依托单位: ADVANCED IMMUNE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2010-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570092
• 关键词: Autoimmune Diseases; Autoimmune Process; Cell surface; Cells; Complication; Development; Disease; Gene Transfer; Glycoproteins; Growth Factor; Human; Human Characteristics; Individual; Infiltration; Inflammation; Kidney; Kidney Diseases; Laboratories; Leukocytes; Lupus; Lupus Nephritis; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Mediating; Morbidity - disease rate; Mus; Nephritis; Pathogenesis; Pathway interactions; Patients; Protein Isoforms; Proteoglycan; Renal Circulation; Role; Signal Transduction; Source; Systemic Lupus Erythematosus; Testing; Therapeutic; Tissues; base; macrophage; mortality; therapeutic target

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..

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品系的小鼠自发地发展类似于SLE的疾病。已经表明，巨噬细胞（MO）在MRL-Faslpr株的狼疮肾炎中是突出的，并且在活化时，MO在炎症期间破坏肾驻留细胞。集落刺激因子-1（CSF-1）是促进MRL-Faslpr小鼠狼疮性肾炎所必需的主要MO生长因子。CSF-I的作用仅由CSF-I受体（CSF-IR）介导。存在三种单独的CSF-1同种型，细胞表面CSF-1（csCSF）、分泌的蛋白聚糖（spCSF）和分泌的糖蛋白（sgCSF）。我们推测，CSF-1和CSF-1 R轴承细胞是中央狼疮肾炎的发病机制。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MRL-Faslpr小鼠中的狼疮肾炎和系统性疾病; 2）确定单个CSF-1同种型在MRL-Faslpr小鼠中的狼疮肾炎和系统性疾病中的作用;和3）确定在MRL-Faslpr小鼠疾病期间消除CSF-1信号传导是否可以阻止狼疮肾炎和系统性疾病的进展。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率和死亡率的主要原因。这种炎症在很大程度上是由称为巨噬细胞的白色血细胞亚群介导的，巨噬细胞破坏肾脏内的组织。已经表明，CSF-1，主要的巨噬细胞生长因子，促进小鼠的肾脏炎症，这些小鼠自发地发展出一种具有人类狼疮许多特征的疾病。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通路是否是人类狼疮和其他巨噬细胞介导的肾脏疾病的潜在治疗靶点。