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CD40 monocyte in chronic kidney disease

CD40单核细胞在慢性肾脏病中的作用

基本信息

批准号：
9897533
负责人：
Hong Wang
金额：
$ 71.4万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897533
关键词：
Adult Affect Antibodies Aorta Apolipoprotein E Atherosclerosis Blood Blood Vessels CD14 gene CD40 Ligand Cardiovascular Diseases Cardiovascular system Cell surface Cells Cessation of life Cholesterol Chronic Chronic Kidney Failure DNA DNA Methylation Data Development Disease End stage renal failure FCGR3B gene Folic Acid General Population Glucose Homocysteine Human Hyperhomocysteinemia Immune Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Knowledge Lead Link Mediator of activation protein Metabolic Methylation Molecular Mus Nephrectomy Pathogenesis Patients Peripheral Blood Mononuclear Cell Phagocytes Phenotype Population Procedures Production Reagent Renal function Reporting Research Risk Factors Role Severity of illness Spleen Splenocyte Stimulus TNFRSF5 gene Testing Therapeutic Tissues Toxin Transplantation Vascular Diseases Vascular remodeling base cytokine human model improved inhibitor/antagonist monocyte mortality mouse model new therapeutic target novel novel therapeutics prevent promoter response success therapeutic evaluation vascular inflammation

项目摘要

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.

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，慢性肾脏病小鼠模型以及尿毒症毒素处理的人/小鼠外周血单个核细胞中。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。