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.

概括：慢性肾病 (CKD) 是一种常见疾病，影响超过 15% 的美国成年人口心血管死亡率比一般人群高10至30倍。我们最近发现了一种新的炎症单核细胞亚群 CD40 单核细胞 (MC)，它具有很强的炎症特征，并且在 CKD 患者中升高。我们确定CD40+ MC为小说炎症性 MC 子集在 CKD 受试者中升高。额外的初步数据使我们得出假设 CKD 和尿毒症毒素通过 CD40 配体诱导 CD40+ 炎症 MC 分化诱导 CD40 表达、CD40 启动子上的 DNA 低甲基化，以及 2) CD40 抑制，炎症小体抑制和 DNA 甲基化治疗可以逆转 CD40+ MC 分化，血管炎症和动脉粥样硬化。我们将使用三个相互关联的目标来检验这个假设。目的 1 将研究 CKD 对人类和人类的 CD40+ MC 分化和组织炎症的影响 CKD 小鼠模型以及尿毒症毒素处理的人/小鼠 PBMC 中。目标 2 将检查 CKD 诱导 CD40+ MC 分化的分子机制。目标 3 将测试 CD40 阻断、Casp1 抑制和 DNA 甲基化对 CD40+ MC 的治疗益处 CKD 的分化、动脉粥样硬化和肾功能。拟议研究的完成情况将导致识别 CKD 和心血管之间的基本机制联系疾病和新的治疗靶点。