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Kidney Keratins, endogenous cytoprotective factors?

肾脏角蛋白、内源性细胞保护因子？

基本信息

批准号：
318056912
负责人：
Professor Dr. Peter Boor, Ph.D.
金额：
--
依托单位：
Institut für Pathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/318056912?language=en
关键词：
Kidney Keratins endogenous cytoprotective factors

项目摘要

Keratins (K) are intermediate filaments (IFs) and a major component of the cell cytoskeleton of epithelial cells, providing for their mechanical integrity. Keratins also have cytoprotective functions in a variety of stress situations, best described for skin and the gastrointestinal tract. Tubular cells (TEC) are the most abundant renal epithelial cells. During virtually all kidney diseases TEC are exposed to a number of stress stimuli, to which they react by phenotypic alterations and cytoskeletal remodeling. We recently showed that the major renal keratins, i.e. K7, K8, K18 and K19, are highly up-regulated in different animal models and patients with kidney injury and could serve as novel markers of TEC stress. We hypothesize, that keratins may play a major cytoprotective role during the accommodation of TEC to a broad array of stress situations and that they promote TEC repair. We aim to tackle this hypothesis in the following work packages:1. We will compare wild-type and various keratin-deficient primary murine TEC in vitro with respect to biomechanical properties, phenotypic and pro-inflammatory alterations, regenerative potential and survival.2. In vivo, we will analyze the consequences of deletion of the whole keratin II gene cluster specifically in TEC or of single major renal keratins in healthy mice and in several renal disease models characterized by TEC injury and regeneration. 3. We will use the K8-eYFP reporter mice to analyze the dynamics of keratin filaments in vitro and in vivo.4. Finally, we aim to identify the post-translational modifications and potential novel kidney keratins and test the usefulness of keratins as specific urinary markers of TEC injury.These experiments will provide first data on the functional role and diagnostic potential of renal keratins.

角蛋白（K）是上皮细胞的中间丝（IF）和细胞骨架的主要组分，提供它们的机械完整性。角蛋白在各种应激情况下也具有细胞保护功能，最好描述为皮肤和胃肠道。肾小管细胞（TEC）是最丰富的肾上皮细胞。在几乎所有的肾脏疾病中，TEC都暴露于许多应激刺激，它们通过表型改变和细胞骨架重塑对其作出反应。我们最近发现，主要的肾角蛋白，即K7，K8，K18和K19，在不同的动物模型和肾损伤患者中高度上调，可以作为TEC应激的新标志物。我们推测，角蛋白可能发挥了重要的细胞保护作用，在适应TEC的广泛的压力的情况下，他们促进TEC修复。我们的目标是在以下工作包中解决这个假设：1。我们将在体外比较野生型和各种角蛋白缺陷的原代小鼠TEC的生物力学特性、表型和促炎性改变、再生潜力和存活率。在体内，我们将分析整个角蛋白II基因簇特异性地在TEC或单个主要的肾角蛋白在健康小鼠和在几个肾脏疾病模型的TEC损伤和再生的特点删除的后果。3. 我们将使用K8-eYFP报告基因小鼠分析角蛋白丝在体外和体内的动力学. 最后，我们的目标是确定翻译后修饰和潜在的新的肾角蛋白和测试角蛋白作为TEC损伤的特异性尿液标记物的有用性。这些实验将提供第一个数据的功能作用和肾角蛋白的诊断潜力。