CD40 monocyte in chronic kidney disease

总结： 慢性肾病（CKD）是一种常见疾病，影响>15%的美国成年人口， 心血管死亡率是普通人群的10 - 30倍。我们最近 发现了一种新的炎性单核细胞亚群CD 40单核细胞（MC）， 炎症特征，并在CKD患者中升高。我们确定CD 40 + MC为一种新的 在CKD受试者中升高的炎性MC亚群。额外的初步数据使我们 假设CKD和尿毒症毒素通过CD 40配体诱导CD 40+炎性MC分化 诱导的CD 40表达，CD 40启动子上的DNA低甲基化，和2）CD 40抑制， 炎性小体抑制和DNA甲基化治疗可以逆转CD 40 + MC分化， 血管炎症和动脉粥样硬化。我们将用三个相互关联的目标来检验这个假设。目的 1将研究CKD对人CD 40 + MC分化和组织炎症的影响， CKD的小鼠模型，以及尿毒症毒素处理的人/小鼠PBMC。目标2将检查 CKD诱导CD 40 + MC分化的分子机制目标3将测试 CD 40阻断、Casp 1抑制和DNA甲基化对CD 40 + MC的治疗益处 分化、动脉粥样硬化和肾功能。完成拟议的研究 将导致确定CKD和心血管疾病之间的基本机制联系 疾病和新的治疗靶点。

Summary: Chronic kidney disease (CKD) is a common disease affecting >15% of the US adult population and has cardiovascular mortality10- to 30-folds greater than that in general population. We recently discovered a novel inflammatory monocyte subset the CD40 monocyte (MC) that has strong inflammatory feature and is elevated in CKD patients. We determined CD40+ MC as a novel inflammatory MC subset which is elevated in CKD subjects. Additional preliminary data lead us to hypothesize that CKD and uremic toxins induce CD40+ inflammatory MC differentiation via CD40 ligand induced CD40 expression, DNA hypomethylation on CD40 promoter, and 2) CD40 Inhibition, inflammasome suppression and DNA methylation therapy can reverse CD40+ MC differentiation, vascular inflammation and atherosclerosis. We will test this hypothesis using three connected Aims. Aim 1 will investigate the effect of CKD on CD40+ MC differentiation and tissue inflammation in human and mouse models of CKD, and in uremic toxin-treated human/mouse PBMC. Aim 2 will examine molecular mechanism underlying CKD-induced CD40+ MC differentiation. Aim 3 will test the therapeutic benefit of CD40 blocking, Casp1 inhibition and DNA methylation on CD40+ MC differentiation, atherosclerosis and kidney function in CKD. Accomplishment of the proposed research will lead to the identification of fundamental mechanistic links between CKD and cardiovascular disease, and novel therapeutic targets.