RENAL OSTEODYSTROPHY AND VASCULAR CALCIFICATION

肾骨质营养不良和血管钙化

• 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
• 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

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）：目前主要关注新近认识到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脏疾病（CKD）与骨骼、血管系统和心脏联系起来的病理生理学新原理。病理生理学的重要进展将在这一应用中得到追求，新的肾脏治疗药物的疗效将在新的转化模型中确定，以接近心血管风险。新的病理生理学发现，其机制必须被发现：首先，在早期CKD导致CKD- mbd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。在第二个目标中，将确定肾损伤通过骨骼导致心血管功能受损的机制。在第三个目标中，将寻求磷（Pi）通过BMP-2激活的异位血管成骨程序刺激动脉粥样硬化血管钙化的机制。CKD降低血管平滑肌细胞、成骨细胞和足细胞的分化表型。CKD刺激细胞迁移到动脉粥样硬化斑块导致矿化的异位成骨细胞程序。高磷血症是CKD影响的驱动因素之一，其作用机制是刺激血管中成骨细胞特异性转录因子活性。然而，抑制高磷血症的作用降低了骨近端的成骨程序。该应用程序的长期目标是通过攻击病理生理机制来追求慢性肾脏疾病并发症的治疗。本应用程序的研究将解决核心假设，即骨骼是CKD相关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。这一假设将在早期CKD中得到验证，因为CKD会导致两种新激素系统的失调和血管钙化的刺激。其中一种新的激素调节能量利用，骨钙素的变化对心脏能量利用的影响将在目标2中进行研究。在目标三，如何降低血清Pi抑制血管平滑肌细胞成骨转化将被确定。本申请的具体目的是：1)确定CKD早期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成骨转化相互作用的分子基础。