CARDIOVASCULAR RISK MECHANISMS IN CKD

CKD 的心血管风险机制

基本信息

批准号：
8372642
负责人：
KEITH A HRUSKA
金额：
$ 33.06万
依托单位：
WASHINGTON UNIVERSITY
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：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8372642
关键词：
Antibodies Aorta Arterial Fatty Streak Biological Markers Blood Circulation Blood Vessels Bone Diseases Bone remodeling Calcitriol Calcium Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cells Chronic Kidney Failure Complication Consensus Control Animal Deposition Development Disease Disease Association Functional disorder General Population Goals Guidelines Homeostasis Hormones Injury Intervention Kidney Kidney Diseases Kidney Failure Laboratories Link Metabolism Minerals Modeling Morbidity - disease rate Names Nature Observational Study Osteoblasts Osteocytes Osteogenesis Outcome Parathyroid gland Pathogenesis Pathway interactions Phosphorus Plant Roots Prevention Production Quality of life Renal Osteodystrophy Research Risk Role Secondary Hyperparathyroidism Serum Skeleton Staging Syndrome Testing Vascular calcification Vitamin D calcification cardiovascular risk factor effective intervention improved inhibitor/antagonist inorganic phosphate mortality neutralizing monoclonal antibodies pandemic disease prevent programs repaired skeletal skeletal circulation skeletal disorder transcription factor

项目摘要

DESCRIPTION (provided by applicant): There is a current ongoing pandemic of chronic kidney disease (CKD). CKD is associated with high mortality rates related to cardiovascular complications associated with kidney disease. The nature of the cardiovascular risk in CKD is incompletely understood, but CKD stimulated vascular calcification and vascular stiffness are important components. Observational studies suggest that the serum phosphate is associated with mortality risk in CKD, and that the association is due to the relationship between hyperphosphatemia and vascular calcification. Recent studies have suggested that the serum phosphorus is associated with cardiovascular risk in the general population, and the role of Pi as a cardiovascular risk factor has been supported by our discovery of putative mechanisms of action in traslational studies. Hyperphosphatemia, in part deriving from the skeleton, stimulates osteoblastic transition of cell in atherosclerotic plaques leading to vascular calcification. In CK hyperphosphatemia stimulated the expression of a second osteoblast specific transcription factor, osterix in the atherosclerotic aorta, and increased vascular calcification. These studies were the first to suggest that the skeleton participated in vascular calcification in CKD. An important complication of CKD linked to vascular calcification and cardiovascular risk is the adynamic bone disorder. New pathophysiology linking kidney disease to the adynamic bone disorder will be pursued in this application. Recent studies demonstrate that CKD causes reactivation and release to the circulation of skeletal inhibitory factors. This concept will be pursued in the application. The long-range objective of this application is to pursue treatment of chronic kidney disease complications through attacking the mechanisms of pathophysiology. The central hypothesis of the application is that kidney disease directly inhibits skeletal functio causing the CKD-MBD, and that the CKD-MBD is a critical factor in the cardiovascular complications of CKD. The specific aims of the application are to: 1) Determine the mechanisms of skeletal inhibition produced by CKD: The hypothesis of aim one is that kidney disease directly inhibits skeletal function by producing circulating factors that decrease bone formation. 2) Determine the mechanisms by which the CKD-MBD causes cardiovascular risk in CKD. The hypotheses of aim two are that the skeletal remodeling disorder produced by CKD causes stimulation of cardiovascular complications associated with kidney diseases, and that interventions, which normalize skeletal remodeling in CKD but have no direct vascular efficacy actions, will diminish the cardiovascular disease associated with kidney failure. PUBLIC HEALTH RELEVANCE: The studies proposed in this application prove that kidney disease releases substances into the bloodstream that migrate to the skeleton where they inhibit bone formation. The second set of studies show how decreasing bone formation increases calcium deposits in blood vessels causing them to become stiff.

描述（由申请人提供）：目前慢性肾病（CKD）正在流行。 CKD 与肾脏疾病相关心血管并发症的高死亡率有关。 CKD 心血管风险的本质尚不完全清楚，但 CKD 刺激的血管钙化和血管僵硬度是重要组成部分。观察性研究表明，血清磷酸盐与 CKD 的死亡风险相关，这种关联是由于高磷血症和血管钙化之间的关系所致。最近的研究表明，血清磷与一般人群的心血管风险相关，并且我们在翻译研究中发现的假定作用机制也支持了 Pi 作为心血管风险因素的作用。高磷血症部分源自骨骼，刺激动脉粥样硬化斑块中细胞的成骨细胞转变，导致血管钙化。在 CK 中，高磷血症刺激动脉粥样硬化主动脉中另一种成骨细胞特异性转录因子 osterix 的表达，并增加血管钙化。这些研究首次表明骨骼参与了 CKD 中的血管钙化。与血管钙化和心血管风险相关的 CKD 的一个重要并发症是动力性骨病。本申请将寻求将肾脏疾病与动力性骨疾病联系起来的新病理生理学。最近的研究表明，CKD 会导致骨骼抑制因子重新激活并释放到循环中。这一概念将在应用中得到贯彻。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。该申请的中心假设是肾脏疾病直接抑制骨骼功能导致CKD-MBD，并且CKD-MBD是CKD心血管并发症的关键因素。该申请的具体目的是： 1) 确定 CKD 产生的骨骼抑制机制：目标一的假设是肾脏疾病通过产生减少骨形成的循环因子来直接抑制骨骼功能。 2) 确定 CKD-MBD 导致 CKD 心血管风险的机制。目标二的假设是，CKD 产生的骨骼重塑障碍会刺激与肾脏疾病相关的心血管并发症，而使 CKD 骨骼重塑正常化但没有直接血管功效作用的干预措施将减少与肾脏相关的心血管疾病失败。公共健康相关性：本申请中提出的研究证明，肾脏疾病会向血液中释放物质，这些物质会迁移到骨骼中，从而抑制骨形成。第二组研究表明，骨形成减少如何增加血管中的钙沉积，导致血管变硬。