Molecular mechanisms of uremia-associated modulation of inflammation in chronic kidney disease.

慢性肾病尿毒症相关炎症调节的分子机制。

• 批准号: 261914061
• 负责人: Professor Dr. Alexander Zarbock
• 金额: --
• 依托单位: Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/261914061?language=en
• 关键词: Molecular; mechanisms; uremia; associated; modulation

Loss of renal function is associated with a pro-¬inflammatory milieu and a concomitantly impaired immune system. In patients with chronic kidney disease (CKD), the uremia-associated defect in the immune system has a broad clinical impact on morbidity and mortality. These patients are highly susceptible to infections and have an increased risk of atherosclerosis. Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. However, the molecular mechanisms of uremia-associated altered leukocyte recruitment and inflammatory response are yet unknown. Therefore, the aim of the proposal is to identify how chronic uremia in the context of CKD may affect integrin activity and the different steps of leukocyte recruitment by using gene-deficient mice, retrovirus technology, and biochemical methods. As the levels of fibroblast growth factor (FGF)-23 increase in patients with CKD, we will investigate the effects of FGF23 on leukocyte functions. In addition, we will perform a clinical trial and confirm our findings in patients with CKD. Further understanding of the role of uremia-associated altered leukocyte recruitment and activation is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.

肾功能丧失与促炎环境和伴随的免疫系统受损相关。在慢性肾脏病（CKD）患者中，尿毒症相关的免疫系统缺陷对发病率和死亡率具有广泛的临床影响。这些患者对感染高度敏感，并且动脉粥样硬化的风险增加。白细胞向发炎组织的募集以级联方式进行。中性粒细胞与内皮的第一次接触是由选择素及其反受体介导的，随后是滚动和整合素介导的停滞。当滚动时，中性粒细胞收集不同的炎症信号，其可以激活导致整合素激活、白细胞粘附到内皮和迁移到发炎组织中的几种途径。然而，尿毒症相关的白细胞募集和炎症反应的分子机制尚不清楚。因此，该提案的目的是通过使用基因缺陷小鼠、逆转录病毒技术和生物化学方法来确定慢性尿毒症在CKD背景下如何影响整合素活性和白细胞募集的不同步骤。随着CKD患者成纤维细胞生长因子（FGF）-23水平的升高，我们将研究FGF 23对白细胞功能的影响。此外，我们将进行临床试验，并确认我们在CKD患者中的发现。进一步了解尿毒症相关的白细胞募集和激活的作用是必要的，以治疗靶向特定分子和抑制白细胞的特定功能，而不影响他人。