Mechanisms of Notch1 in Aortic Valve Calcification

Notch1在主动脉瓣钙化中的作用机制

• 批准号: 7561331
• 负责人: VISHAL NIGAM
• 金额: $ 13.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561331
• 关键词: Adult; Age; Aortic Valve Stenosis; Apoptosis; Bicuspid; Blood Vessels; Calcified; Calcium; Cardiac; Cardiovascular system; Cell Differentiation process; Cells; Computer Systems Development; Condition; Data; Deposition; Developed Countries; Developing Countries; Disease; Disruption; Event; Family; Family member; Gender; Gene Expression; Genes; Heart; Heart Diseases; Human; Hyperlipidemia; Hypertension; Immune system; In Vitro; Incidence; Infiltration; Inflammatory; Knockout Mice; Laboratories; Link; Lipids; Lipoproteins; Mediating; Mesenchymal; Mesenchyme; Molecular; Mus; Mutation; Myofibroblast; NOTCH1 gene; Osteoblasts; Osteogenesis; Pathologic; Pathway interactions; Pattern; Play; Pregnancy; Reporting; Repression; Risk Factors; Role; Signal Pathway; Signal Transduction; Smoking; Stenosis; Stress; Tissues; Work; abstracting; aortic valve; calcification; hemodynamics; macrophage; male; malformation; mouse model; notch protein; relating to nervous system; response; shear stress; vascular bed

DESCRIPTION (provided by applicant): Aortic valve calcification/stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. The risk factors most closely linked to calcific aortic stenosis are the presence of a bicuspid aortic valve, increased age, male gender, smoking, hypertension, and elevated lipoproteins. Examination of human calcified aortic valve tissue has shown that several pathologic pathways are involved. However, the molecular mechanisms involved in valvular calcification have not been elucidated. Recently, the Srivastava lab reported two human families in which mutations in NOTCH1 were associated with early calcification of the aortic valve and bicuspid aortic valves. Notchl is a part of a highly conserved signaling pathway involved in many cellular events, including cell fate decisions and cell differentiation. This study demonstrated that Hrt2, a transcriptional represser that mediates the Notchl signal, could regulate the activity of Runx2, a central regulator of osteoblast cell fate determination in vitro. Our preliminary data show that Notchl heterozygous mice develop increased aortic valve calcification as compared to wild-type age matched littermates. I hypothesize that Notchl signaling represses pro-osteogenic pathways in aortic valve mesenchyme and that Notchl disruption may sensitize the valve to known risk factors that promote calcification. Specific Aim 1: To determine if disrupting Notchl signaling causes calcification of the aortic valve by activation of osteogenic pathways in mice. Notchl signaling will be conditionally disrupted in aortic valve tissue valves prenatally or postnatally. The aortic valves will be examined for functional stenosis, calcification, and expression of genes involved in bone formation. In addition, Notchl-deficient mice will be crossed with a mouse model of hyperlipidemia to examine the contribution of this risk factor to Notchl-mediated aortic valve calcification. Specific Aim 2: To elucidate the calcific pathways mediated by Notchl in mesenchymal and endocardial cells. Notchl expression will be disrupted or enhanced in cultured mesenchymal and endocardial cells under various conditions. Mesenchymal cells will be examined for activation or repression of osteoblast-specific gene expression and in some cases deposition of calcium. The interactions between Notchl signaling and three molecular pathways previously implicated in cardiovascular calcification, namely Runx2, Bmp2, and Wnt, will be examined. (End of Abstract)

描述（由申请人提供）： 主动脉瓣钙化/狭窄是成人心脏病的第三主要原因，也是发达国家获得的瓣膜疾病的最常见形式。与钙化主动脉狭窄最紧密联系的危险因素是存在双质主动脉瓣，年龄增加，男性性别，吸烟，高血压和脂蛋白升高。对人钙化的主动脉瓣组织的检查表明，涉及几种病理途径。但是，尚未阐明参与瓣膜钙化的分子机制。最近，Srivastava实验室报告了两个人类家庭，其中Notch1中的突变与主动脉瓣和双质主动脉瓣的早期钙化有关。 Notchl是许多细胞事件中涉及的高度保守信号通路的一部分，包括细胞命运的决策和细胞分化。这项研究表明，HRT2是介导Notchl信号的转录阻遏物，可以调节Runx2的活性，Runx2是成骨细胞命运的中心调节剂，并在体外确定。我们的初步数据表明，与野生型年龄相比，Notchl杂合小鼠会增加主动脉瓣钙化。我假设NOTCHL信号传导在主动脉瓣间充质中抑制促骨途径，而Notchl破坏可能会使瓣膜敏感到促进钙化的已知危险因素。具体目标1：确定是否破坏NOTCHL信号传导是否通过激活小鼠的成骨途径而导致主动脉瓣的钙化。 NOTCHL信号将在产前或产后有条件地在主动脉瓣组织瓣膜中受到干扰。将检查主动脉瓣的功能狭窄，钙化和与骨形成有关的基因的表达。此外，缺乏缺陷的小鼠将与高脂血症的小鼠模型交叉，以检查这种危险因素对Notchl介导的主动脉瓣钙化的贡献。具体目标2：阐明在中质和心内膜细胞中Notchl介导的钙化途径。在各种条件下，在培养的间质细胞和心内膜细胞中，NOTCHL表达将被破坏或增强。将检查间充质细胞的激活或抑制成骨细胞特异性基因表达，在某些情况下钙的沉积。将检查NOTCHL信号传导与先前与心血管钙化有关的三个分子途径之间的相互作用，即RUNX2，BMP2和WNT。 （抽象的结尾）