MDM-2 in glomerular and interstitial kidney disease

MDM-2 在肾小球和间质性肾病中的作用

• 批准号: 155180533
• 负责人: Professor Dr. Hans-Joachim Anders
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik IV
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/155180533?language=en
• 关键词: MDM; glomerular; interstitial; kidney; disease

During the first funding period we described the p53-dependent pro-mitotic effects of MDM2 as well as, at first, the p53-independent pro-inflammatory effects. The MDM2 antagonist nutlin-3a dramatically improved experimental lupus nephritis, post-ischemic tubular necrosis, and focal-segmental glomerulosclerosis. However, MDM2 blockade impaired post-ischemic tubular-regeneration and had no effect on diabetic nephropathy. As we found MDM2 to be expressed predominantely in renal epithelial cells, we plan to use the second funding period to study the functional role of MDM2 in renal epithelia in more detail. We plan to 1. produce podocyte-, tubular cell, and monocyte-specific MDM2-deficient mice, 2 to characterize their spontaneous phenotype (homeostatic role of epithelial MDM2), 3. induce experimental models of glomerular and tubular injury (pathophysiological role of epithelial MDM2), and 4. to create each of these knockout mice in a cell type-specific p53+/+ or p53-/- manner to dissect the bifunctional role of MDM2. The analysis of all these mice will enable us to understand how renal epithelial cells handle stress signals in physiological and pathophysiological settings in terms of inflammation and regeneration. We speculate the constitutive expression of MDM2 to be an important element of renal epithelial homeostasis and repair.

在第一个资助期内，我们首先描述了MDM2的p53依赖性促有丝分裂作用以及p53非依赖性促炎症作用。MDM2拮抗剂nutlin-3a可显著改善实验性狼疮性肾炎、缺血后肾小管坏死和局灶节段性肾小球硬化。然而，MDM2阻断会损害缺血后小管再生，对糖尿病肾病没有影响。由于我们发现MDM2主要在肾上皮细胞中表达，我们计划利用第二个资助期更详细地研究MDM2在肾上皮中的功能作用。我们计划……产生足细胞、小管细胞和单核细胞特异性MDM2缺陷小鼠2，以表征其自发表型（上皮MDM2的稳态作用），3。3 .诱导肾小球和小管损伤的实验模型（上皮MDM2的病理生理作用）；以细胞类型特异性p53+/+或p53-/-的方式创建这些敲除小鼠，以解剖MDM2的双重功能作用。对所有这些小鼠的分析将使我们能够了解肾上皮细胞如何在炎症和再生方面的生理和病理生理环境中处理应激信号。我们推测MDM2的组成表达是肾上皮稳态和修复的重要因素。