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.

摘要