The Role of Notch in Calcific Aortic Valve Disease

切迹在钙化性主动脉瓣疾病中的作用

• 批准号: 9143866
• 负责人: Vidu Garg
• 金额: $ 67.71万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143866
• 关键词: Address; Affect; Attenuated; Biochemical; Biological Assay; Biological Availability; Biotin; Calcium; Cell physiology; Cells; Cessation of life; Cre-LoxP; DNA Binding; Data; Defect; Deposition; Development; Disease; Endothelial Cells; Endothelium; Epidemiologic Studies; Functional disorder; Genes; Genetic; Goals; Heart Valve Diseases; Heart Valves; Homeostasis; Human; In Vitro; Individual; Knowledge; Lead; Left; Ligand Binding; Ligands; Link; Longitudinal Studies; Mediating; Membrane; Molecular; Molecular Biology; Movement; Mus; Mutation; N Domain; NOS3 gene; NOTCH1 gene; Nitric Oxide; Nitric Oxide Donors; Nodule; Nuclear; Operative Surgical Procedures; Osteoblasts; Pathogenesis; Pathway interactions; Penetrance; Pharmacological Treatment; Play; Point Mutation; Prevention Measures; Process; Production; Public Health; Publications; Publishing; Regulation; Repression; Research; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Stenosis; System; Testing; Therapeutic; United States; abstracting; aging population; aortic valve; aortic valve disorder; base; bone; calcification; clinical risk; clinically significant; hemodynamics; improved; in vivo; innovation; interstitial cell; jagged1 protein; mouse model; new therapeutic target; notch protein; novel; novel therapeutics; osteogenic; prevent; programs; receptor; success; tool

Abstract: Calcific aortic valve disease is increasingly recognized as an active cellular process that is regulated by a distinct molecular program. Epidemiologic studies have identified numerous clinical risk factors, which result in endothelial cell dysfunction marked by reduced nitric oxide bioavailability, that predispose the valve to calcification. In addition, there is an increasing amount of evidence that valve interstitial cells respond to endothelial cell dysfunction by transforming into osteoblast-like cells, resulting in calcium deposition on aortic valve cusps. Currently, a significant knowledge gap exists in our molecular understanding of how endothelial cells communicate with the underlying valve interstitial cells (VICs) to promote osteogenic-like changes. This knowledge deficit hinders the development of new therapies for calcific aortic valve disease. The basis of this proposal is the discovery by our group that mutations in NOTCH1 cause calcific aortic valve disease in humans. Furthermore we have shown that reduced nitric oxide signaling from the valve endothelium promotes the calcification of valve interstitial cells by a Notch1-mediated mechanism. In addition, the NO and Notch1 signaling pathways display genetic interaction as mice homozygous null for endothelial nitric oxide synthase (eNOS, or Nos3) and heterozygous for Notch1 have aortic valve thickening and abnormal hemodynamics similar to humans, at ~100% penetrance. Our long-term goal is to utilize this novel molecular pathway for the development of novel therapeutics to prevent or slow calcific aortic valve disease. The overall objective of this application is to define the mechanisms by which defects in endothelial NO signaling regulate Notch1 in valve interstitial cells and promote osteogenic changes and calcification. The central hypothesis is: In CAVD, decreased endothelial nitric oxide bioavailability decreases nitrosylation of the Notch1 receptor and Notch1 intracellular domain (N(1)ICD nuclear localization in valve interstitial cells. As a result, Notch activity is reduced, causing calcification. Guided by our publications and preliminary data, the central hypothesis will be tested by pursuing three Specific Aims: 1) Define the temporal development of aortic valve disease in Notch1+/-;Nos3-/- mice, and determine the therapeutic potential of NO donor treatment; 2) Determine if endothelial cell-Jag1 is required to regulate Notch1 activity in VICs and determine its requirement in valve homeostasis in vivo; 3) Define the molecular mechanisms by which endothelial cell-derived nitric oxide (NO) regulates Notch1 signaling in VICs to prevent calcification. Success of this proposal will open multiple new avenues for potential therapies for calcific aortic valve disease. The proposed research is significant because it not only characterizes a novel molecular pathway linking the valve endothelium to the process of calcification of valve interstitial cells but also establishes a new mouse model for longitudinal studies of aortic valve calcification. The knowledge gained will be used to improve prevention measures and develop new therapies for calcific aortic valve disease.

摘要：钙化主动脉瓣疾病越来越被认为是一种活跃的细胞过程 由独特的分子程序调节。流行病学研究已经确定了许多临床风险 因素，导致内皮细胞功能障碍以降低的一氧化氮生物利用度的标志性， 易感瓣膜钙化。另外，有越来越多的证据表明阀门 间质细胞通过转化为成骨细胞样细胞来应对内皮细胞功能障碍，从而导致 主动脉瓣膜上的钙沉积。目前，我们的分子存在很大的知识差距 了解内皮细胞如何与下面的瓣膜间隙细胞（VIC）通信 促进类似成骨的变化。这种知识赤字阻碍了新疗法的发展 钙化主动脉瓣疾病。 该提案的基础是我们小组发现Notch1中的突变引起钙化主动脉 人类的瓣膜疾病。此外，我们已经证明了阀门的一氧化氮信号的减少 内皮通过Notch1介导的机制促进瓣膜间质细胞的钙化。此外， NO和NOTCH1信号通路显示遗传相互作用，作为内皮纯合无效的小鼠 一氧化氮合酶（ENOS或NOS3）和Notch1的杂合子具有主动脉瓣增厚和异常 与人类类似的血液动力学，约100％的渗透率。我们的长期目标是利用这种新颖的分子 开发新型治疗剂以预防或缓慢的钙化主动脉瓣疾病的途径。总体 该应用的目的是定义内皮中缺陷无信号调节的机制 瓣膜间质细胞中的Notch1并促进成骨的变化和钙化。 中心假设是：在CAVD中，内皮一氧化氮生物利用度降低 Notch1受体和Notch1细胞内结构域的硝基化（n（1）ICD核定位 阀间质细胞。结果，缺口活性减少，导致钙化。由我们的指导 出版物和初步数据，将通过追求三个具体目标来检验中心假设：1） 定义Notch1 +/-; nos3 - / - 小鼠中主动脉瓣疾病的时间发育，并确定 没有供体治疗的治疗潜力； 2）确定是否需要内皮细胞-JAG1进行调节 Notch1在VIC中的活性，并确定其在体内瓣膜稳态中的需求； 3）定义分子 内皮细胞衍生的一氧化氮（NO）调节VIC中的Notch1信号的机制，以防止 钙化。该提案的成功将为钙化主动脉的潜在疗法开放多种新途径 瓣膜疾病。拟议的研究很重要，因为它不仅表征了一种新颖的分子 将阀内皮与瓣膜间隙细胞的钙化过程联系起来的途径 建立一个新的小鼠模型，用于主动脉瓣钙化的纵向研究。获得的知识将 可用于改善预防措施并开发新的钙化主动脉瓣疾病疗法。