Investigating the Role of Sclerostin in Calcific Aortic Valve Disease

研究硬化素在钙化主动脉瓣疾病中的作用

• 批准号: 10330041
• 负责人: Jeffery E Joll
• 金额: $ 0.44万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330041
• 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; TNFSF11 gene; Testing; Tissues; analog; aortic valve; aortic valve disorder; blood pump; calcification; cardiovascular effects; 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.

摘要 Romosozumab是一种靶向硬化蛋白的单克隆抗体，最近的临床试验表明， 在降低骨质疏松症患者骨折风险方面非常有效。然而，心血管副作用 一直是FDA批准该药的主要障碍，并可能阻碍其在临床疾病中的应用 管理虽然最初认为硬化蛋白只在骨骼中表达，但最近的研究表明， 已经证实其在心血管组织、细胞和疾病中表达。与流通相关的研究 硬化蛋白与心血管疾病的关系一直很复杂很少有研究硬化素的机制， 心血管疾病的研究已经发表，但没有人研究过这种蛋白质在主动脉瓣健康中的作用 尽管这种蛋白质是在患病的瓣膜中发现的。钙化性主动脉瓣疾病（CAVD）是 心脏瓣膜最常见的疾病，在老年人群中越来越普遍。这是一个 众所周知，这种疾病很难研究和治疗，每年造成大约15，000人死亡， 北美CAVD的发病机制的特征在于纤维钙化病变的逐渐积累， 降低了顺应性和难以将血液泵入体循环。不进行瓣膜置换，CAVD 会导致心力衰竭而死亡有迫切需要解开这一分子病理生理学 为了研制出有效的药物。我们实验室的初步结果表明硬化蛋白 在小鼠模型中CAVD的发展中所必需的。此外，瓣膜间质细胞转移到疾病 在体外用蛋白质处理时的表型。我们假设硬化蛋白是CAVD的驱动因素， 激活RANKL-NFκB信号通路，导致纤维化和营养不良性钙化 瓣膜间质细胞该提案的目标是更好地了解硬化蛋白在CAVD中的作用，并评估 其作为药理学靶点的潜力。本研究提出了两个主要目标：1）多尺度分子 Sost基因突变小鼠CAVD表型的表征2）在预处理中研究瓣膜疾病， 绝经后骨质疏松症中sclerostin阻断的临床类似物。这项研究将是第一个确定 硬化素在主动脉瓣健康和疾病中的分子机制。深入分析基因和 硬化蛋白信号传导的药理学减少将提供对观察到的副作用的了解， 骨质疏松症治疗以及治疗CAVD的潜力。