NEPHROTOXIC NEPHRITIS IN CCR5 AND CXCR3 KNOCKOUT MICE

CCR5 和 CXCR3 敲除小鼠中的肾毒性肾炎

• 批准号: 6667079
• 负责人: OMAR M FITURI
• 金额: $ 4.94万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6667079
• 关键词: IP 10 protein; blood chemistry; cell cell interaction; chemokine; chemotaxis; cytokine receptors; disease /disorder etiology; disease /disorder model; disease /disorder onset; dissection; fibrosis; foreign body reaction; genetically modified animals; glomerulonephritis; helper T lymphocyte; histology; laboratory mouse; leukocytes; macrophage inflammatory proteins; nephritis; protein protein interaction; receptor expression; renal glomerulus; renal toxin; urinalysis

Glomerular inflammation, crescent formation and interstitial fibrosis, the major features of severe glomerulonephritis (GN), are mediated by the infiltration of leukocytes. This infiltrate results from the coordinated release of a number of chemotatic. Recently much attention has focused on the role of chemokines in this disease. Studies in humans have shown up-regulation of several chemokines (RANTES, MIP-1beta, MCP-1) and chemokine receptors (CCR5, CXCR3) in renal glomeruli and interstitium but their functional role remains largely undefined. Similarly, studies in animal models of inflammatory GN have shown up-regulation of several chemokines and chemokine receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, IP10, and lymphotactin (fractalkine), and the chemokine receptors. CCR1, CCR2, CCR5, and CXCR3 are highly expressed in models of crescentic GN. In addition, chemokines and their receptors influence the balance between the Th1 and Th2 helper T cell subsets. This in turn may alter the severity of experimental crescentic GN, which results from a predominantly TH1 response. We hypothesize in this proposal that disrupting CCR5 or CXCR3 will affect the development of glomerular crescents and post-inflammatory interstitial fibrosis in a murine model of crescentic GN and alter the balance between Th1 and Th2 in the response to exogenous antigen. We plan to test this hypothesis in an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the development and progression of GN and the initiating immune response will have important implications for the design of therapies to neutralize these potent inflammatory mediators in glomerular and other autoimmune diseases.

肾小球炎症、新月体形成和间质纤维化是严重肾小球肾炎（GN）的主要特征，是由白细胞浸润介导的。这种渗透是由许多趋化剂的协调释放引起的。最近，很多注意力集中在趋化因子在这种疾病中的作用。人类研究表明肾小球和间质中的几种趋化因子（RANTES、MIP-1beta、MCP-1）和趋化因子受体（CCR5、CXCR3）上调，但它们的功能作用在很大程度上仍不清楚。同样，炎症性肾小球肾炎动物模型的研究表明，几种趋化因子和趋化因子受体在疾病的不同阶段上调。特别是疾病不同阶段的趋化因子、MIP1-β、MCP-1、RANTES、MIP-2、eotaxin、受体。特别是疾病不同阶段的趋化因子、MIP1-β、MCP-1、RANTES、MIP-2、eotaxin、受体。特别是趋化因子、MIP1-β、MCP-1、RANTES、MIP-2、eotaxin、IP10 和淋巴趋化素 (fractalkine) 以及趋化因子受体。 CCR1、CCR2、CCR5 和 CXCR3 在新月体 GN 模型中高度表达。此外，趋化因子及其受体影响 Th1 和 Th2 辅助 T 细胞亚群之间的平衡。这反过来可能会改变实验性新月体 GN 的严重程度，而实验性新月体 GN 是由 TH1 反应为主的结果。我们在此提议中假设，破坏 CCR5 或 CXCR3 将影响新月体肾小球肾炎小鼠模型中肾小球新月体的发育和炎症后间质纤维化，并改变 Th1 和 Th2 对外源抗原反应中的平衡。我们计划在使用缺乏 CCR5 或 CXCR3 的小鼠的鼠肾毒性肾炎加速模型中测试这一假设，并与使用缺乏 CCR5 或 CXCR3 的小鼠与野生型对照相比的鼠肾毒性肾炎加速模型进行比较。研究破坏这两种趋化因子受体及其配体对野生型对照的影响。研究破坏这两种趋化因子受体及其配体对肾小球肾炎的发生和进展以及启动免疫反应的影响，对于设计中和肾小球和其他自身免疫性疾病中这些强效炎症介质的疗法具有重要意义。