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

CKD-MBD 病理生理学和治疗的新进展

• 批准号: 10609908
• 负责人: KEITH A HRUSKA
• 金额: $ 42.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609908
• 关键词: Activin A type II receptor; Activin Receptor; Activins; Address; Affect; Aorta; Binding; Blood Vessels; Bone Diseases; Bone Formation Stimulation; Bone Resorption; Calcitriol; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Wall; Cells; Chronic Kidney Failure; Circulation; Clinical Trials; Complication; Disease; Disease model; FGFR4 gene; Family; Family member; Functional disorder; General Population; Goals; Heart; Heart Diseases; Heart Hypertrophy; Hyperparathyroidism; Injury to Kidney; Investigation; Kidney; Kidney Diseases; Laboratories; Lead; Ligands; Mesenchymal Stem Cells; Minerals; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Names; Nephrons; Organ; Osteoblasts; Osteocytes; Pathogenesis; Process; Production; Quality of life; Regulation; Renal Osteodystrophy; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction; Skeleton; Syndrome; Systemic disease; TNFSF11 gene; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Type II Activin Receptors; Validation; Vascular Diseases; Vascular calcification; Vitamin D Analog; Work; activin A; bone; calcification; cardiovascular disorder risk; disease mechanisms study; effective intervention; fibroblast growth factor 23; improved outcome; inhibitor; inorganic phosphate; kidney fibrosis; kidney repair; knock-down; member; mortality; mortality risk; novel; novel therapeutics; osteoblast differentiation; pandemic disease; prevent; receptor; release factor; repaired; restoration; skeletal; therapeutic target; transcription factor; transcriptome

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.

抽象的 我们最近的研究建立了一个新的范式，即慢性肾病——矿物质骨疾病 (CKD-MBD) 综合征部分是由尝试肾脏修复过程中诱导的因子释放引起的。 流通。这些研究表明 CKD 和 IIA 型激活素受体 (ActRIIA) 的全身激活 确定 ActRIIA 信号传导作为 CKD-MBD 和肾纤维化的潜在治疗靶点。慢性肾病 疾病（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 成分。 CKD-MBD 综合征是一种常见的并发症 严重肾损伤后开始的 CKD 会使 GFR 降低 10% 或更多。可用的治疗方案 攻击 CKD-MBD - 磷酸盐结合剂、维生素 D 类似物和拟钙剂，针对晚期阶段 综合征而不是其发病机制或直接的心血管并发症，并且未能显示 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确定。慢性肾病 调节脉管系统、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。本申请中的研究建议 确定 ActRIIA 在 CKD 中被激活的机制，重点关注 Activin 的配体刺激 A. 诱导敲低策略和激活素 A 单克隆抗体将用于确定 CKD 中 ActRIIA 激活中的激活素 A。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 的治疗作用 CKD-MBD 血管钙化的目标。在骨骼目标 2 研究中，CKD 的机制受到刺激 寻找成骨细胞功能障碍以及骨吸收和异常重塑。在心脏目标 3 研究中， CKD 刺激心脏肥大的机制将重点关注心脏能量学和 周氧体增殖物激活受体-γ 共激活因子-1α (PGC-1α) 的调节证实了其作用 ActRIIA 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作为 ActRIIA 的激活素 A 引起的 配体，将其确立为 CKD-MBD 和 CKD 的治疗靶点，并支持以下领域的新临床试验 CKD-MBD 和 CKD 的进展。