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，即慢性肾脏疾病-矿物性骨病 (CKD-MBD)综合征的部分原因是在尝试肾脏修复过程中诱导的因子释放到 发行量。这些研究表明，激活素受体IIA型(ActRIIA)在CKD和 确定ActRIIA信号是CKD-MBD和肾脏纤维化的潜在治疗靶点。慢性肾脏 疾病(CKD)是一种与高心血管死亡率相关的大流行。高涨的原因 心血管死亡风险包括CKD-MBD组分。CKD-MBD综合征是一种常见的并发症 在严重的肾脏损伤后开始的CKD会使GFR降低10%或更多。可用的治疗方案 攻击CKD-MBD-磷酸粘合剂、维生素D类似物和仿钙剂，针对 证候而不是其发病机制或心血管并发症的直接表现，并未显示 在临床试验中对心血管有益。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确定。CKD 调节血管、心脏、骨骼和肾脏中的ActRIIA信号。ActRIIA信令有助于 肾脏疾病的血管、骨骼和心脏并发症。本申请中的研究建议 明确ActRIIA在CKD中激活的机制，重点是激活蛋白对配体的刺激 A.可诱导的基因敲除策略和抗激活素A的单抗将被用来确定 激活素A在慢性肾脏病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AIM 1研究将证实ActRIIA是一种治疗方法 靶点在CKD-MBD的血管钙化。在骨骼AIM 2研究中，CKD的刺激机制 寻求成骨细胞功能障碍、骨吸收和异常重塑。在心脏目标3研究中， CKD引起心肌肥厚的机制将从心脏能量学和心肌肥厚机制两个方面进行探讨。 周氧体增殖物激活受体-γ共激活物-1α(PGC-1α)的调节作用 ActRIIA，并确认其为治疗靶点。成功完成拟议的研究将确立 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，使其成为CKD-MBD和CKD的治疗靶点，并支持新的临床试验 CKD-MBD在CKD进展中的作用。

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.