Interference of the cold shock protein YB-1 and progranulin on tumor necrosis factor-alpha signalling in inflammatory renal disease

Y-box结合蛋白-1(YB-1)属于人类冷休克蛋白超家族。它的已知功能与允许细胞表型变化和细胞间交流的基因转录和RNA翻译有关。有证据表明，炎症性肾病中YB-1的表达与细胞因子的合成有关。我们的数据表明，在系膜增生性疾病模型中，系膜细胞表达YB-1，甚至分泌活跃的蛋白质，以及YB-1与抗炎蛋白原相互作用。目前的建议旨在研究YB-1：原颗粒蛋白相互作用在炎症性肾病中的功能作用(S)。首先，我们将讨论YB-1如何影响原颗粒的抗炎活性。接下来，我们将研究YB-1或原颗粒的缺失是否会改变炎症性肾病的发生或发展。此外，我们将测试操纵YB-1水平是否会改变炎症性肾病的进程。最后，我们将确定原颗粒蛋白和肿瘤坏死因子α水平是否是炎症性肾病活动的合适标记物。该提案解决了YB-1和原颗粒蛋白在炎症性肾脏疾病发病机制中的功能作用(S)的关键问题，并可能为诊断和治疗策略开辟新的途径。

Y-box binding protein-1 (YB-1) belongs to the human cold shock protein superfamily. Its known functions relate to gene transcription and RNA translation that permit cell phenotypic changes and cell-cell communication. Evidence links YB-1 expression with cytokine synthesis in inflammatory kidney disease. Our data demonstrate a pronounced mesangial cell expression of YB-1 and even active protein secretion in models of mesangioproliferative disease, as well as an interaction of YB 1 with the anti-inflammatory protein progranulin. The current proposal aims to investigate the functional role(s) of the YB-1:progranulin interaction in inflammatory kidney disease. First we will address how YB-1 influences the anti-inflammatory activity of progranulin. Next we shall investigate whether the loss of YB-1 or progranulin alters the onset or progression of inflammatory kidney disease. Additionally, we shall test whether manipulating YB-1 levels alter the course of inflammatory kidney disease. And finally, we shall determine whether progranulin and tumor necrosis factor alpha levels are suitable markers for inflammatory kidney disease activity. The proposal addresses pivotal questions on the functional role(s) of YB-1 and progranulin in the pathogenesis of inflammatory kidney diseases and may open new avenues to diagnostic and therapeutic strategies.