RANK-RANKL and Vascular Complications in Chronic Kidney Disease

RANK-RANKL 与慢性肾脏病的血管并发症

基本信息

批准号：
9096751
负责人：
MICHAEL E ROSENFELD
金额：
$ 50.25万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096751
关键词：
Acceleration Accounting American Heart Association Aorta Arterial Fatty Streak Atherosclerosis Binding Blood Vessels Bone Marrow Transplantation Calcified Cardiovascular Diseases Cardiovascular system Cells Cholesterol Chronic Kidney Failure Coculture Techniques Complex Dendritic Cells Development Dialysis procedure End stage renal failure General Population Genes Guns High Fat Diet Homeostasis Human Hypertension Inflammatory Interleukin-6 Lead Lesion Ligands Lipids Macrophage Activation Mediator of activation protein Membrane Metabolism Molecular Mus Osteoclasts Osteoporosis Oxidative Stress Pathology Pathway interactions Patients Play Population Proteins Proteome Proteomics Public Health Risk Risk Factors Role Serum Signal Transduction Smooth Muscle Myocytes Syndrome System TNF gene Testing Therapeutic Tumor necrosis factor receptor 11b United States Uremia Vascular Diseases Vascular calcification base bone calcification calcium phosphate cardiovascular risk factor cell type cytokine feeding high risk human data macrophage mineralization monocyte mortality mouse model new therapeutic target public health relevance receptor receptor expression trend

项目摘要

DESCRIPTION (provided by applicant): There is a highly significant increase in mortality from cardiovascular disease due to accelerated development of atherosclerosis and vascular calcification in people with chronic kidney disease. Traditional risk factors for cardiovascular disease don't entirely explain these accelerated vascular pathologies. We have shown that there is accelerated development of atherosclerosis and vascular calcification in mice that are deficient in osteoprotegerin, a decoy receptor for the receptor activator of NFkB ligand (RANKL). RANK-RANKL plays an essential role in bone homeostasis by stimulating the differentiation of osteoclasts. We have also shown that uremic LDLR-/- mice fed a high fat diet have accelerated atherosclerotic lesion development and increased expression of RANK in the aorta. Furthermore, treatment of macrophages and dendritic cells with RANKL stimulates the secretion of pro-inflammatory cytokines. We now hypothesize that the accelerated development of atherosclerosis and vascular calcification in chronic kidney disease may be due to increased RANKL and the stimulation of RANK signaling in macrophages and dendritic cells. We will test this hypothesis with 2 specific aims. In aim 1, we will determine the signature of secreted proteins using shot-gun proteomics and the profile of expressed genes using microarrays in macrophages and dendritic cells from uremic mice and monocytes from people with chronic kidney disease as well as in macrophages and dendritic cells treated with RANKL in order to determine which pro-atherosclerotic and pro-calcification pathways are activated and may account for the accelerated vascular disease. In the second aim, we will transplant bone marrow from mice that are deficient in RANK into uremic mice and treat uremic mice with an anti-RANKL therapeutic (OPG-Fc) to determine whether blocking RANKL can protect against the accelerated atherosclerosis and vascular calcification that occurs with chronic kidney disease.

描述（由申请人提供）：由于患有慢性肾脏病患者的动脉粥样硬化和血管钙化的加速发展，心血管疾病的死亡率高度显着增加。心血管疾病的传统危险因素并不能完全解释这些加速的血管病理。我们已经表明，在骨蛋白蛋白蛋白蛋白蛋白酶（NFKB配体的受体激活剂（RANKL））的诱饵受体（RANKL）中，小鼠动脉粥样硬化和血管钙化的发展加速了。排名通过刺激破骨细胞的分化在骨稳态中起着至关重要的作用。我们还表明，喂食高脂肪饮食的尿毒症LDLR - / - 小鼠已加速了动脉粥样硬化病变的发育和主动脉中等级的表达增加。此外，用RANKL治疗巨噬细胞和树突状细胞会刺激促炎细胞因子的分泌。现在，我们假设慢性肾脏疾病中动脉粥样硬化和血管钙化的加速发展可能是由于RANKL的增加以及巨噬细胞和树突状细胞中等级信号传导的刺激。我们将以2个特定目标检验这一假设。在AIM 1中，我们将使用Shot-Gun蛋白质组学确定分泌蛋白质的特征，以及使用巨噬细胞中的微阵列和来自尿毒症小鼠和树突状细胞中的微阵列的表达基因的特征，以及来自患有慢性肾脏疾病的人的单核细胞，以及在巨噬细胞中，以及在巨噬细胞和树突状细胞中，以确定可能会引起行动的Procrifation Protivation Protivation Pation Pation Pation Pation Pation Pation Pation Pation Pathertotial carcrccal，血管疾病。在第二个目标中，我们将从小鼠中移植骨髓骨髓，这些小鼠缺乏排名级的小鼠，并使用抗裂痕治疗（OPG-FC）治疗尿毒症小鼠，以确定封闭RANKL是否可以预防与慢性肾脏疾病发生的相关动脉粥样硬化和血管钙化。