RENAL OSTEODYSTROPHY AND VASCULAR CALCIFICATION

肾骨质营养不良和血管钙化

基本信息

批准号：
8503607
负责人：
KEITH A HRUSKA
金额：
$ 22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-23 至 2014-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8503607
关键词：
Abbreviations Address Arterial Fatty Streak Arteries Atherosclerosis Attention Automobile Driving Biology Blood Blood Vessels Bone Diseases Calcitriol Calcium Cardiac Cardiomyopathies Cardiovascular Pathology Cardiovascular Physiology Cardiovascular system Cell Differentiation process Cells Chronic Kidney Failure Congestive Heart Failure Consensus Coronary Arteriosclerosis Deposition Development Disease Endocrine system Endopeptidases Equilibrium Event Excess Mortality Extracellular Matrix Failure Foundations Functional disorder Funding General Population Grant Heart Heart Diseases Heart failure Homeobox Homologous Gene Hormones Hyperplasia Injury Kidney Kidney Diseases Kidney Failure Lead Left Ventricular Hypertrophy Link Low Density Lipoprotein Receptor Medial Minerals Modeling Molecular Morbidity - disease rate Myocardial Infarction Nature Organ Osteoblasts Osteocalcin Osteogenesis Outcome Outcome Study Parathyroid gland Patients Peripheral Phenotype Phosphorus Physiology Polymerase Chain Reaction Prevention approach Prevention therapy Pulse Pressure Regulation Renal Osteodystrophy Research Reverse Transcriptase Polymerase Chain Reaction Reverse Transcription Role Serum Skeleton Smooth Muscle Myocytes Stroke System Systems Biology TNF gene Testing Therapeutic Agents Tumor Necrosis Factor-alpha Tumor necrosis factor receptor 11b Vascular Diseases Vascular Smooth Muscle Vascular calcification Vitamin D3 Receptor X-Ray Computed Tomography base bone bone morphogenetic protein 2 calcification cardiovascular risk factor dentin matrix protein 1 fibroblast growth factor 23 high risk improved inorganic phosphate insight kidney vascular structure mineralization mortality myocardin novel novel therapeutics osteogenic podocyte programs skeletal systolic hypertension transcription factor

项目摘要

DESCRIPTION (provided by applicant): There is a current major focus on the newly recognized cardiovascular risk associated with kidney disease. Recent studies have discovered new principles of pathophysiology linking chronic kidney disease (CKD) to the skeleton, the vasculature and the heart. Important advances arising from pathophysiology will be pursued in this application, and the efficacy of new renal therapeutic agents will be determined in novel translational models to approach the cardiovascular risk. New pathophysiologic discoveries for which mechanisms must be discovered are: first, in early CKD causing the CKD-MBD how does the skeleton contribute to vascular calcification (VC); and how calcitriol blocks CKD stimulated VC and inhibits the actions of hyperphosphatemia. These will be sought in the studies of the first aim. In the second aim, the mechanism of impaired cardiovascular function produced by kidney injury through the skeleton will be determined. In the third aim, the mechanism of phosphorus (Pi) stimulation of vascular calcification through the heterotopic vascular osteogenic program activated by BMP-2 in atherosclerosis will be sought. CKD decreases the differentiated phenotype of vascular smooth muscle cells, osteoblasts, and podocytes. CKD stimulates a heterotopic osteoblast program in cells migrating into atherosclerotic plaques leading to mineralization. Hyperphosphatemia is one of the factors driving the effects of CKD, and its mechanism of action is stimulation of osteoblast specific transcription factor activity in the vasculature. However, suppression of the action of hyperphosphatemia decreased the osteogenic program proximal to osterix. The long-range objective of this application is to pursue treatment of chronic kidney disease complications through attacking the mechanisms of pathophysiology. The studies in this application will address the central hypothesis that the skeleton is a critical organ in the multisystem failure associated with CKD, and that treatment of the CKD-MBD will decrease cardiovascular mortality. The hypothesis will be tested in early CKD which causes disordered regulation of two new hormonal systems and stimulation of vascular calcification. One of the new hormones regulates energy utilization and the effects of changes in osteocalcin on cardiac energy utilization will be studied in aim 2. In aim three, how reduction in the serum Pi suppresses osteoblastic transition of vascular smooth muscle cells will be determined. The specific aims of the application are to: 1) Determine the mechanism of stimulation of vascular calcification in early CKD. 2) Analyze the effect of osteocalcin on cardiac energy utilization and vascular smooth muscle cell differentiation. 3) Determine the molecular basis for the interaction of skeleton with BMP-2/4 stimulated VSMC osteoblastic transition in CKD.

描述（由申请人提供）：当前主要关注的是新认识的与肾脏疾病相关的心血管风险。最近的研究发现了将慢性肾病 (CKD) 与骨骼、脉管系统和心脏联系起来的病理生理学新原理。本申请将追求病理生理学产生的重要进展，并将在新的转化模型中确定新的肾脏治疗药物的功效，以降低心血管风险。必须发现其机制的病理生理学新发现是：首先，在导致 CKD-MBD 的早期 CKD 中，骨骼如何促进血管钙化 (VC)；以及骨化三醇如何阻断 CKD 刺激的 VC 并抑制高磷血症的作用。这些将在第一个目标的研究中寻求。第二个目标是确定通过骨骼肾损伤导致心血管功能受损的机制。第三个目标是寻找动脉粥样硬化中磷 (Pi) 通过 BMP-2 激活的异位血管成骨程序刺激血管钙化的机制。 CKD 降低血管平滑肌细胞、成骨细胞和足细胞的分化表型。 CKD 刺激细胞中的异位成骨细胞程序迁移到动脉粥样硬化斑块中，从而导致矿化。高磷血症是导致 CKD 影响的因素之一，其作用机制是刺激血管系统中成骨细胞特异性转录因子的活性。然而，抑制高磷血症的作用会降低 osterix 附近的成骨程序。该应用的长期目标是通过攻击病理生理学机制来治疗慢性肾病并发症。本申请中的研究将解决一个中心假设，即骨骼是与 CKD 相关的多系统衰竭的关键器官，并且 CKD-MBD 的治疗将降低心血管死亡率。该假设将在早期 CKD 中得到检验，早期 CKD 会导致两种新的激素系统调节紊乱并刺激血管钙化。目标 2 将研究一种新激素调节能量利用，以及骨钙素变化对心脏能量利用的影响。目标三将确定血清 Pi 的减少如何抑制血管平滑肌细胞的成骨细胞转变。该应用的具体目的是： 1) 确定早期 CKD 中血管钙化的刺激机制。 2）分析骨钙素对心脏能量利用和血管平滑肌细胞分化的影响。 3)确定CKD中骨骼与BMP-2/4刺激的VSMC成骨细胞转变相互作用的分子基础。