Novel Advances in the Pathophysiology and Treatment of the CKD-MBD

摘要 我们最近的研究建立了一个新的范式，即慢性肾脏病-矿物质骨紊乱 （CKD-MBD）综合征部分是由在尝试肾修复过程中诱导的因子释放引起的， 流通。这些研究表明，在CKD中激活素受体IIA型（ActRIIA）的全身性激活， 将ActRIIA信号传导确定为CKD-MBD和肾纤维化的潜在治疗靶点。慢性肾脏 慢性肾脏病（CKD）是一种与高心血管死亡率相关的流行病。高的原因 心血管死亡风险包括CKD-MBD组分。CKD-MBD综合征是一种统一的并发症 在严重肾损伤后开始的CKD使GFR降低10%或更多。可用的治疗方案 攻击CKD-MBD -磷酸盐结合剂，维生素D类似物和拟钙剂，靶向晚期阶段， 证候与其发病机制或心血管并发症无直接关系，也未能显示 临床试验中的心血管益处。因此，非常需要与CKD-MBD相关的发现。 CKD-MBD心血管成分的发病机制和治疗靶点的鉴定。CKD 调节血管系统、心脏、骨骼和肾脏中的ActRIIA信号传导。ActRIIA信号传导有助于 肾脏疾病的血管、骨骼和心脏并发症。本申请中的研究提出， 确定ActRIIA在CKD中被激活的机制，重点是激活素对配体的刺激 A.可诱导的敲低策略和激活素A的单克隆抗体将用于确定激活素A的作用。 激活素A在CKD中的ActRIIA激活中的作用。将研究血管、骨骼和心脏组织的机制， ActRIIA激活的疾病和机制。血管目标1研究将验证ActRIIA作为治疗药物 CKD-MBD血管钙化的靶点。在骨骼目标2研究中，CKD刺激的机制 寻找成骨细胞功能障碍和骨吸收以及异常重塑。在心脏aim 3研究中， CKD刺激的心脏肥大的机制将集中于心脏能量学和 通过过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）的调节证实了 并验证其作为治疗靶点。成功完成拟议的研究将建立 CKD-MBD的血管、骨骼和心脏成分是由激活素A作为ActRIIA引起的 配体，将其确立为CKD-MBD和CKD的治疗靶点，并支持在 CKD-MBD和CKD的进展。

Abstract Our recent studies have established a new paradigm that the chronic kidney disease – mineral bone disorder (CKD-MBD) syndrome is partly caused by release of factors that are induced during attempted kidney repair into the circulation. These studies have shown systemic activation of activin receptor type IIA (ActRIIA) in CKD and identified ActRIIA signaling as a potential therapeutic target for the CKD-MBD and renal fibrosis. Chronic Kidney Disease (CKD) is a pandemic associated with high cardiovascular mortality rates. The causes of the high cardiovascular mortality risk include CKD-MBD components. The CKD-MBD syndrome is a uniform complication of CKD beginning after significant kidney injury reduces GFR by 10% or more. The available therapeutic options attacking the CKD-MBD - phosphate binders, vitamin D analogs, and calcimimetics, target late stages of the syndrome and not its pathogenesis or the cardiovascular complications directly, and have failed to show cardiovascular benefit in clinical trials. Thus, there is great need for discoveries related to CKD-MBD pathogenesis and identification of therapeutic targets for the CKD-MBD cardiovascular components. CKD modulates ActRIIA signaling in the vasculature, heart, skeleton and kidney. ActRIIA signaling contributes to vascular, skeletal, and cardiac complications of kidney disease. The studies in this application propose to identify the mechanism by which ActRIIA is activated in CKD focusing on ligand stimulation by Activin A. Inducible knockdown strategies and monoclonal antibody to activin A will be used to determine the role of activin A in ActRIIA activation in CKD. Vascular, skeletal and cardiac tissues will be studied for mechanism of disease and mechanism of ActRIIA activation. The vascular aim 1 studies will validate ActRIIA as a therapeutic target in the vascular calcification of the CKD-MBD. In skeletal aim 2 studies, the mechanism of CKD stimulated osteoblast dysfunction and bone resorption and abnormal remodeling is sought. In the cardiac aim 3 studies, the mechanism of CKD stimulated cardiac hypertrophy will be sought focusing on cardiac energetics and the regulation by perioxosome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) confirming the role of ActRIIA and validating it as a therapeutic target. Successful completion of the proposed studies will establish that the vascular, skeletal and cardiac components of the CKD-MBD are caused by activin A as an ActRIIA ligand, establishing it as a therapeutic target in the CKD-MBD and CKD, and support new clinical trials in the CKD-MBD and in the progression of CKD.