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：钙化性主动脉瓣病变日益被认为是一种活跃的细胞过程，即 受不同的分子程序调控。流行病学研究已经确定了许多临床风险 导致内皮细胞功能障碍的因素，以一氧化氮生物利用度降低为标志， 使瓣膜易于钙化。此外，越来越多的证据表明，瓣膜 间质细胞对内皮细胞功能障碍的反应是转化为成骨样细胞，导致 主动脉瓣尖端钙质沉积。目前，我们的分子中存在着一个重大的知识鸿沟 了解内皮细胞如何与基础瓣膜间质细胞(VIC)沟通以 促进成骨样改变。这种知识缺失阻碍了新疗法的开发 钙化性主动脉瓣病。 这一建议的基础是我们团队的发现，NOTCH1基因突变导致主动脉钙化 人类的瓣膜病。此外，我们还表明，来自瓣膜的一氧化氮信号减少 内皮细胞通过Notch1介导的机制促进瓣膜间质细胞钙化。此外, NO和Notch1信号通路表现为小鼠内皮细胞纯合子缺失的遗传交互作用 一氧化氮合酶(eNOS，或NOS3)和Notch1杂合子可导致主动脉瓣增厚和异常 血流动力学与人类相似，外显率约为100%。我们的长期目标是利用这种新的分子 开发预防或减缓钙化性主动脉瓣疾病的新疗法的途径。整体而言 这项应用的目的是确定内皮细胞NO信号缺陷调节的机制 NOTCH1在瓣膜间质细胞中并促进成骨改变和钙化。 中心假说是：在CAVD中，内皮一氧化氮的生物利用度降低 Notch1受体亚硝化与Notch1胞内结构域(N(1)ICD)核定位 瓣膜间质细胞。结果，Notch活性降低，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) 确定Notch1+/-；NOS3-/-小鼠主动脉瓣疾病的时间发展，并确定 NO供体治疗的治疗潜力；2)确定是否需要内皮细胞-Jag1调节 NOTCH1在VICS中的活性及其在活体瓣膜动态平衡中的需求；3)确定分子 血管内皮细胞源性一氧化氮调节血管内皮细胞Notch1信号转导机制 钙化。这项提议的成功将为钙化性主动脉的潜在治疗开辟多种新的途径 瓣膜病。这项拟议的研究意义重大，因为它不仅描述了一种新的分子 将瓣膜内皮细胞与瓣膜间质细胞钙化过程联系起来的途径 建立一种新的小鼠主动脉瓣钙化纵向研究模型。所获得的知识将 用于改进预防措施和开发钙化性主动脉瓣疾病的新疗法。