CARDIOVASCULAR RISK MECHANISMS IN CKD

CKD 的心血管风险机制

• 批准号: 8507216
• 负责人: KEITH A HRUSKA
• 金额: $ 31.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/8507216
• 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

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.

描述（由申请人提供）：目前存在慢性肾脏疾病（CKD）的持续大流行。 CKD与与肾脏疾病相关的心血管并发症有关的高死亡率有关。 CKD中心血管风险的性质尚不完全了解，但是CKD刺激的血管钙化和血管僵硬是重要的成分。观察性研究表明，血清磷酸盐与CKD的死亡率风险有关，并且该关联是由于高磷酸血症与血管钙化之间的关系。最近的研究表明，血清磷与一般人群中的心血管风险有关，并且通过发现误认为作用机理的假定作用机理，PI作为心血管危险因素的作用得到了支持。过度磷酸血症部分源自骨骼，刺激细胞在动脉粥样硬化斑块中导致血管钙化的成骨细胞过渡。在CK高磷酸化中，刺激了第二成骨细胞特异性转录因子的表达，动脉粥样硬化主动脉中的osterix和增加的血管钙化。这些研究是第一个表明骨骼参与CKD中血管钙化的研究。与血管钙化和心血管风险相关的CKD的重要并发症是动力骨障碍。在本应用中将探讨将肾脏疾病与肾脏骨疾病联系起来的新病理生理学。最近的研究表明，CKD引起重新激活并释放骨骼抑制因子的循环。该概念将在应用程序中追求。该应用的远距离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。该应用的中心假设是肾脏疾病直接抑制引起CKD-MBD的骨骼功能，并且CKD-MBD是CKD心血管并发症的关键因素。该应用的具体目的是：1）确定CKD产生的骨骼抑制的机制：目标的假设是，肾脏疾病通过产生降低骨形成的循环因子直接抑制骨骼功能。 2）确定CKD-MBD在CKD中引起心血管风险的机制。目标二的假设是，由CKD产生的骨骼重塑疾病会导致刺激与肾脏疾病相关的心血管并发症，而干预措施将CKD中的骨骼重塑正常化，但没有直接的血管功效作用，这会减少与儿童失败相关的心血管疾病。