Role of SIRT6 in calcific aortic valve disease

SIRT6 在钙化性主动脉瓣疾病中的作用

基本信息

批准号：
8439626
负责人：
Jordan D Miller
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-04 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439626
关键词：
Acetylation Affect Age Aging Animal Model Aortic Valve Stenosis Attenuated Bone Matrix Calcified Calcium Cardiovascular system Cell Aging Cell Differentiation process Cells Data Deacetylase Deposition Development Disease Disease-Free Survival Elderly Endothelial Cells Endothelium Enzymes Epigenetic Process Functional disorder Gene Expression Gene Expression Profile Genes Glean Goals Health Histone Acetylation Human Hydrogen Peroxide Hypertension In Vitro Inflammation Innovative Therapy Left Lesion Link Longevity Methods Modification Morbidity - disease rate Mus Neural Crest Neural Crest Cell Operative Surgical Procedures Osteoblasts Osteoclasts Oxidative Stress Patients Phenotype Play Population Process Protein Acetylation Proteins Regulation Reporting Risk Factors Role Signal Transduction Sirtuins Smoking Stem cells Stenosis Syndrome Tissues Vascular Endothelium Ventricular Work age related aortic valve aortic valve disorder autocrine base calcification catalase human tissue hypercholesterolemia improved in vivo interest interstitial cell mortality mouse model novel osteogenic overexpression paracrine promoter public health relevance recombinase valve replacement

项目摘要

DESCRIPTION (provided by applicant): Aging is associated with progressive increases in cardiovascular calcification1. Hemodynamically significant aortic valve stenosis affects 3% of the population over age 65. Patients with even moderate aortic valve stenosis (peak velocity of 3-4 m/sec) have a 5 year event-free survival of less than 40%, with the only approved treatment being valve replacement surgery. Recent work, however, described the presence of osteoblast-like cells, osteoclast-like cells, and bone matrix in calcified aortic valves, which suggests that valve calcification is an active, potentially modifiable process. Preliminary data from our group suggest that there are substantial epigenetic modifications present in cells from calcified aortic valves. Specifically, expression of sirtuin 6 is markedly reduced in stenotic valves and strongly associated with increases in protein and histone acetylation. Experimentally, global deletion of SIRT6 in mice results in a dramatic progeroid phenotype, and patients with progeroid syndromes have a much greater propensity for development of cardiovascular calcification. As many risk factors for valve calcification are associated with increases in oxidative stress, we also sought to determine whether there is a link between increases in oxidative stress and histone acetylation/sirtuin activity. Thus, the aims of the current application is to experimentall determine whether: 1) increases in oxidative stress increase histone acetylation and accelerate progression of aortic valve calcification and stenosis, 2) altering SIRT6 levels accelerates or slows progression of aortic valve stenosis in hypercholesterolemic mice, and 3) deletion of SIRT6 in vascular endothelium or neural crest-derived cells (i.e., cells that form the aortic valve and outflow tract) accelerate progression of CAVS. We will use a combination of novel in vivo animal models and in vitro methods to identify mechanisms whereby oxidative stress and SIRT6 impact osteoblast/osteoblast-like cell differentiation and activity in aortic valves. By using thes approaches to identify mechanisms that slow the progression of calcific aortic valve disease, we hope to identify therapies that will improve both the lifespan and health span of humans.

描述（由申请人提供）：衰老与心血管钙化的进行性增加有关。血液动力学显着的主动脉瓣狭窄影响65岁以上的3％的人口。甚至中度主动脉瓣狭窄（峰值速度为3-4 m/sec）的患者的5年无事件生存率小于40％，唯一批准的是瓣膜替代手术。然而，最近的工作描述了钙化主动脉瓣中成骨细胞样细胞，破骨细胞样细胞和骨基质的存在，这表明瓣膜钙化是一种有效的，潜在的可修改过程。来自我们组的初步数据表明，来自钙化主动脉瓣的细胞中存在实质性的表观遗传修饰。具体而言，Sirtuin 6的表达在狭窄瓣膜中明显降低，并且与蛋白质和组蛋白乙酰化的增加密切相关。在实验上，小鼠中SIRT6的全球缺失会导致剧烈的后代表型，而后代综合征的患者对心血管钙化的发展倾向更大。由于瓣膜钙化的许多风险因素与氧化应激的增加有关，因此我们还试图确定氧化应激的增加与组蛋白乙酰化/SIRTUIN活性之间是否存在联系。因此，当前应用的目的是实验确定：1）氧化应激的增加是否增加了组蛋白乙酰化并加速主动脉瓣钙化和狭窄的进展，2）改变SIRT6水平会加速或放慢高胆固醇小鼠中主动脉瓣膜瓣膜的进展，以及3）SERTIREL-CRERTIRED CREDIRER-SERTORTION CREDIRER-SERTIRER-CRERTIRER-CREDIRER-CREDIRER-CREDIRER-SERTORTION CREDIRER-CREDIRER-CREDIRER-SERTIRER cRSTIRER cRSTIRER cRSTIRER-SIRTIRER 6）cRSTIRTIOL 6）。（即形成主动脉瓣的细胞和流出道）加速了骑士的进展。我们将使用新型的体内动物模型和体外方法的组合来识别机制，从而氧化应激和SIRT6会影响成骨细胞/成骨细胞样细胞分化和主动脉瓣中的活性。通过使用这些方法来识别降低钙化主动脉瓣疾病进展的机制，我们希望确定可以改善人类寿命和健康跨度的疗法。