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: 10298983
• 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/10298983
• 关键词: Activin A type II receptor; Activin Receptor; Activins; Address; Affect; Aorta; Binding; Blood Circulation; Blood Vessels; Bone Diseases; Bone Formation Stimulation; Bone Resorption; Calcitriol; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Wall; Cells; Chronic Kidney Failure; 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; base; bone; calcification; cardiovascular disorder risk; disease mechanisms study; effective intervention; fibroblast growth factor 23; improved outcome; inhibitor/antagonist; 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 我们最近的研究确立了一种新的范式，即慢性肾脏疾病 - 矿物质骨疾病 （CKD-MBD）综合征部分是由于释放肾脏修复期间诱导的因素引起的 循环。这些研究表明，CKD和 确定Actriia信号是CKD-MBD和肾纤维化的潜在治疗靶标。慢性儿童 疾病（CKD）是与高心血管死亡率相关的大流行。高高的原因 心血管死亡率风险包括CKD-MBD组件。 CKD-MBD综合征是一种均匀的并发症 CKD在重大肾脏损伤后开始将GFR降低10％或更多。可用的治疗选择 攻击CKD -MBD-磷酸盐粘合剂，维生素D类似物和钙测定法，目标阶段的晚期 综合征，而不是其发病机理或心血管并发症，但未显示 临床试验中的心血管益处。那是非常需要与CKD-MBD相关的发现 CKD-MBD心血管成分的病理和鉴定。 CKD 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。该申请建议中的研究 确定在CKD中激活Actriia的机制，该机制重点是激活素。 A.诱导型敲低策略和对激活素A的单克隆抗体将用于确定 CKD中的actriia激活中激活素A。血管，骨骼和心脏组织将研究机理 Actriia激活的疾病和机制。血管目标1研究将验证actriia作为一种疗法 CKD-MBD的血管计算中的目标。在骨骼目标2研究中，CKD的机制刺激了 成骨细胞功能障碍和骨骼分辨率和异常重塑被伤痕累累。在心脏目标3研究中， CKD刺激心脏肥大的机制将被感知到心脏能量学和 通过周期毒素增殖物激活的受体伽马共振剂1α（PGC-1α）调节，证实了该作用 Actriia并将其验证为治疗靶标。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活化素A作为actriia引起的 配体在CKD-MBD和CKD中将其确立为治疗靶点，并支持新的临床试验 CKD-MBD和CKD的进展。