Investigating the Role of Sclerostin in Calcific Aortic Valve Disease

研究硬化蛋白在钙化性主动脉瓣疾病中的作用

• 批准号: 9911657
• 负责人: Jeffery E Joll
• 金额: $ 4.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911657
• 关键词: Ablation; Acute; Adoption; Adverse effects; Aging; Antibodies; Aortic Aneurysm; Aortic Valve Stenosis; Area; Atherosclerosis; Atomic Force Microscopy; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Cessation of life; Clinical; Clinical Trials; Complement; Complex; Data; Development; Disease; Disease Management; Dystrophic Calcification; Echocardiography; Event; Female; Femur; Fibrosis; Food and Drug Administration Drug Approval; Functional disorder; Future; Genetic; Genotype; Goals; Health; Heart; Heart Valves; Heart failure; Histology; In Vitro; Incidence; Individual; Investigation; Lead; Lesion; Literature; Mechanics; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Mutant Strains Mice; Mutation; Myofibroblast; North America; Osteoporosis; Osteoporotic; Ovariectomy; Pathogenesis; Patients; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Population; Postmenopausal Osteoporosis; Process; Property; Proteins; Publishing; Recombinant Proteins; Research; Risk; Role; Running; Serum; Severity of illness; Signal Induction; Signal Pathway; Signal Transduction; Skeleton; Structure; TNFSF11 gene; Testing; Tissues; analog; aortic valve; aortic valve disorder; blood pump; calcification; cardiovascular health; disease phenotype; experimental study; fracture risk; genetic analysis; improved; individualized medicine; insight; interstitial cell; microCT; molecular pathology; mouse development; mouse model; novel therapeutics; overexpression; patient population; pre-clinical; prevent; side effect; spine bone structure; valve replacement; western diet; Ablation; Acute; Adoption; Adverse effects; Aging; Antibodies; Aortic Aneurysm; Aortic Valve Stenosis; Area; Atherosclerosis; Atomic Force Microscopy; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Cessation of life; Clinical; Clinical Trials; Complement; Complex; Data; Development; Disease; Disease Management; Dystrophic Calcification; Echocardiography; Event; Female; Femur; Fibrosis; Food and Drug Administration Drug Approval; Functional disorder; Future; Genetic; Genotype; Goals; Health; Heart; Heart Valves; Heart failure; Histology; In Vitro; Incidence; Individual; Investigation; Lead; Lesion; Literature; Mechanics; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Mutant Strains Mice; Mutation; Myofibroblast; North America; Osteoporosis; Osteoporotic; Ovariectomy; Pathogenesis; Patients; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Population; Postmenopausal Osteoporosis; Process; Property; Proteins; Publishing; Recombinant Proteins; Research; Risk; Role; Running; Serum; Severity of illness; Signal Induction; Signal Pathway; Signal Transduction; Skeleton; Structure; TNFSF11 gene; Testing; Tissues; analog; aortic valve; aortic valve disorder; blood pump; calcification; cardiovascular health; disease phenotype; experimental study; fracture risk; genetic analysis; improved; individualized medicine; insight; interstitial cell; microCT; molecular pathology; mouse development; mouse model; novel therapeutics; overexpression; patient population; pre-clinical; prevent; side effect; spine bone structure; valve replacement; western diet

Abstract Recent clinical trials for Romosozumab, a monoclonal antibody targeting the protein sclerostin, have shown it to be highly effective in reducing fracture risk in patients with osteoporosis. However, cardiovascular side effects have been a major roadblock in FDA approval of the drug and may hinder its adoption in clinical disease management. Although it was originally believed sclerostin was only expressed in the skeleton, recent studies have demonstrated its expression in cardiovascular tissue, cells, and disease. Research correlating circulating sclerostin to cardiovascular disease has been confounding. Very few studies of the mechanism of sclerostin in cardiovascular disease have been published, and none have examined the protein’s role in aortic valve health and disease, despite the protein being discovered in diseased valves. Calcific aortic valve disease (CAVD) is the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in North America. Pathogenesis of CAVD is characterized by gradual accumulation of fibrocalcific lesions resulting in reduced compliance and difficulty pumping blood to systemic circulation. Without valve replacement, CAVD can lead to death via heart failure. There is an acute need to unravel the molecular pathophysiology of this disease in order to develop efficacious pharmaceuticals. Preliminary results from our lab indicate sclerostin is necessary in the development of CAVD in a mouse model. Additionally, valve interstitial cells shift to a disease phenotype when treated with the protein in vitro. We hypothesize sclerostin is a driver of CAVD through its stimulation of the RANKL-NFκB signaling pathway leading to fibrosis and dystrophic calcification by activated valve interstitial cells. The goal of this proposal is to better understand the role of sclerostin in CAVD and assess its potential as a pharmacological target. This study presents two primary aims: 1) multiscale molecular characterization of the CAVD phenotype of Sost genetic mutant mice 2) investigation of valve disease in a pre- clinical analogue of sclerostin blocking in post-menopausal osteoporosis. This study will be the first to identify the molecular mechanism of sclerostin in aortic valve health and disease. Intensive analysis of genetic and pharmacological reduction of sclerostin signaling will provide insight into the side effects observed in osteoporosis treatment as well as potential for treatment of CAVD.

抽象的 最近针对蛋白质硬化蛋白的单克隆抗体的romosozumab的临床试验已显示为 在降低骨质疏松症患者的骨折风险方面非常有效。但是，心血管副作用 在FDA批准该药物方面一直是主要障碍，并可能阻碍其在临床疾病中的采用 管理。尽管最初认为硬化蛋白仅在骨骼中表达，但最近的研究 已经证明了其在心血管组织，细胞和疾病中的表达。研究相关的循环 心血管疾病的硬化症一直令人困惑。很少有关于硬化素机理的研究 心血管疾病已经发表，没有人检查蛋白质在主动脉瓣健康中的作用 和疾病，DOS在解剖瓣膜中发现的蛋白质。钙化主动脉瓣疾病（CAVD）是 心脏瓣膜最常见的苦难，并且在衰老人群中变得越来越普遍。是一个 臭名昭著的疾病很难研究和治疗，每年约有15,000人死亡 北美。 CAVD的发病机理的特征是导致纤维上病变的等级积累 在降低依从性和困难的血液中，血液循环。没有阀门，Cavd 可以通过心力衰竭导致死亡。急性需要揭示这一点的分子病理生理学 疾病以开发有效的药物。我们实验室的初步结果表明硬化症是 在小鼠模型中开发CAVD所必需的。此外，瓣膜间质细胞转向疾病 表型在体外用蛋白质处理时。我们假设Sclerostin是Cavd的驱动器 刺激RANKL-NFκB信号传导途径，导致激活的纤维化和营养不良钙化 阀间质细胞。该提议的目的是更好地了解硬化蛋白在CAVD和评估中的作用 它作为药物目标的潜力。这项研究提出了两个主要目的：1）多尺度分子 SOST基因突变小鼠的CAVD表型的表征2）在前的瓣膜疾病研究 在绝经后骨质疏松症中硬化蛋白阻塞的临床类似物。这项研究将是第一个识别的 硬化蛋白在主动脉瓣健康和疾病中的分子机制。遗传和 硬化蛋白信号的药理减少将提供对观察到的副作用的见解 骨质疏松治疗以及CAVD治疗的潜力。