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The Role of NOTCH1 Signaling in Aortic Valve Disease.

机译：NOTCH1信号传导在主动脉瓣疾病中的作用。

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摘要

Calcification of the aortic valve is a common disease affecting many people, and requires invasive valve replacement surgery to prevent irreparable damage to the heart. Understanding the molecular mechanisms that contribute to this disease will allow us to hopefully development non-invasive treatments that can slow or reverse this disease process and could potentially help treat the similar and related process of atherosclerosis. Shear stress and NOTCH1 have both been linked to aortic valve calcification and are important regulators of endothelial cell biology. We showed using RNA-seq in primary endothelial cells from human aortic valve, that shear stress controled a genetic program normally responsible for maintaining epiphyseal plates in a proliferative, non-calcified state. In addition, using siRNA knockdown of the NOTCH1 receptor and ChIP-seq, we showed activation of many of these genes including the potent inhibitor of soft tissue calcification, MGP, are directly regulated by NOTCH1 in the endothelium. Furthermore, we developed an efficient method to direct the differentiation of embryonic stem (ES) or induced pluripotent stem (iPS) cells into endothelial cells and determined that this highly pure somatic cell population has limited gene expression variation between cell lines. This method will be used to test human iPS cells derived from patients with valve calcification and NOTCH1 mutations in order to more fully define the mechanism of their disease, and hopefully allow us to directly target important signaling cascades responsible for this ectopic calcification.
机译：主动脉瓣钙化是一种影响许多人的常见疾病，需要进行有创瓣膜置换手术以防止对心脏造成不可修复的损害。了解导致这种疾病的分子机制将使我们有望开发出非侵入性疗法，从而减缓或逆转这种疾病的进程，并有可能帮助治疗动脉粥样硬化的相似及相关过程。剪应力和NOTCH1都与主动脉瓣钙化有关，并且是内皮细胞生物学的重要调节剂。我们证明了在人类主动脉瓣的原代内皮细胞中使用RNA-seq时，剪应力控制着一个遗传程序，该程序通常负责将epi板保持在增生的非钙化状态。此外，使用NOTCH1受体和ChIP-seq的siRNA敲低，我们显示了许多这样的基因的激活，包括有效的软组织钙化抑制剂MGP，它们在内皮细胞中直接由NOTCH1调控。此外，我们开发了一种有效的方法来指导胚胎干（ES）或诱导多能干（iPS）细胞分化为内皮细胞，并确定这种高纯度的体细胞群体在细胞系之间具有有限的基因表达变异。该方法将用于测试具有瓣膜钙化和NOTCH1突变的患者的人iPS细胞，以便更全面地定义其疾病机制，并希望使我们直接靶向负责这种异位钙化的重要信号通路。

著录项

  • 作者

    White, Mark P.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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