The Impact of miR-21 Expression on Endothelial Cell Apoptosis and Inflammation

miR-21表达对内皮细胞凋亡和炎症的影响

基本信息

  • 批准号:
    8391582
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-10-01 至 2014-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Project Summary The purpose of this proposal is to define the influence of microRNA expression on specific changes in endothelial cell function that occur in response to shear stress forces. Shear stress forces, generated by blood flow, play an important role in the regulation of vascular tone, vascular remodeling, and the focal development of atherosclerotic lesions. In the arterial tree, endothelial cells are exposed to different shear stress forces that induce distinct effects on gene expression and function. Unidirectional shear stress, which occurs in the straight part of the tree, elicits a change in endothelial gene expression that is generally anti-inflammatory and atheroprotective. In contrast, oscillatory shear stress, which occurs at branch points in the arterial tree, induces an overall pro-inflammatory and proatherosclerotic response. MicroRNAs (miRNAs) are a recently recognized class of short (19-25 nt), single stranded, noncoding RNAs that have become a major focus in molecular biology research because they posttranscriptionally regulate the expression of genes involved in an array of cell functions, including differentiation, growth, proliferation, and apoptosis. Although an important role for miRNA expression has been demonstrated for various biological processes, including cardiogenesis and angiogenesis, data on the role of specific miRNAs in endothelial cell biology is currently limited. In preliminary studies of human endothelial cells subjected to prolonged unidirectional shear stress (24 hrs, 15 dynes/cm2), a group of miRNAs was identified whose expression was significantly upregulated in response to this stimulus, suggesting that these miRNAs are important in regulating gene expression and function in endothelial cells. To further define the role of miRNA expression in modulating shear stress-induced changes in endothelial cell biology, the function of the most highly regulated miRNA, miR-21, will be studied. Specifically, the proposed experiments will define the impact of miR-21-target gene interaction on shear stress-induced changes in apoptosis and inflammatory molecule expression. Studies will be performed on cultured human endothelial cells subjected to unidirectional and oscillatory shear stress. The activity of apoptotic or inflammation signaling pathways containing miR-21 target genes, such as PI3K/Akt and MAP2K3, will be assessed. Pathway involvement will be tested by experimentally manipulating expression of miR-21, its target gene, or members of the pathway that are downstream of the miRNA-target gene interaction. Subsequently, the effect of these manipulations on endothelial cell apoptosis and adhesion molecule expression will be quantified. Finally, the interaction between miR-21 expression and apoptotic or inflammatory pathway activity will be studied in vivo, in a mouse model of altered aortic flow. We anticipate that these studies will help address a deficit in our knowledge about the function of miRNAs in endothelial cells and will enhance our understanding of the mechanisms by which shear stress forces modulate vascular disease.
描述(由申请人提供): 项目摘要 本提案的目的是确定 microRNA 表达对响应剪切应力而发生的内皮细胞功能特定变化的影响。血流产生的剪切应力在调节血管张力、血管重塑和动脉粥样硬化病变的局灶性发展中发挥着重要作用。在动脉树中,内皮细胞受到不同的剪切应力,这会对基因表达和功能产生不同的影响。发生在树的笔直部分的单向剪切应力会引起内皮基因表达的变化,这种变化通常具有抗炎和动脉粥样硬化的作用。相反,发生在动脉树分支点的振荡剪切应力会诱导整体促炎和促动脉粥样硬化反应。 MicroRNA (miRNA) 是最近公认的一类短 (19-25 nt)、单链非编码 RNA,已成为分子生物学研究的主要焦点,因为它们在转录后调节参与一系列细胞功能的基因的表达,包括分化、生长、增殖和凋亡。尽管已经证明 miRNA 表达对各种生物过程(包括心脏发生和血管生成)具有重要作用,但目前有关特定 miRNA 在内皮细胞生物学中的作用的数据有限。在对人类内皮细胞进行长时间单向剪切应力(24小时,15达因/厘米2)的初步研究中,鉴定出一组miRNA,其表达在这种刺激下显着上调,表明这些miRNA在调节基因表达方面很重要和内皮细胞的功能。为了进一步明确 miRNA 表达在调节剪切应力诱导的内皮细胞生物学变化中的作用,将研究最高度调节的 miRNA miR-21 的功能。具体来说,所提出的实验将确定 miR-21-靶基因相互作用对剪切应力诱导的细胞凋亡和炎症分子表达变化的影响。研究将对培养的人内皮细胞进行单向和振荡剪切应力的研究。将评估包含 miR-21 靶基因(例如 PI3K/Akt 和 MAP2K3)的细胞凋亡或炎症信号传导通路的活性。通路参与将通过实验操纵 miR-21、其靶基因或 miRNA-靶基因相互作用下游通路成员的表达来测试。随后,将量化这些操作对内皮细胞凋亡和粘附分子表达的影响。最后,将在主动脉血流改变的小鼠模型中体内研究 miR-21 表达与细胞凋亡或炎症通路活性之间的相互作用。我们预计这些研究将有助于解决我们对内皮细胞中 miRNA 功能的了解不足,并将增强我们对剪切应力调节血管疾病机制的理解。

项目成果

期刊论文数量(0)
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CHARLES D SEARLES其他文献

CHARLES D SEARLES的其他文献

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{{ truncateString('CHARLES D SEARLES', 18)}}的其他基金

COVID-19: Multi-Omics Approach to Identify Molecular Mechanisms Responsible for Risk and Resilience to Adverse Outcomes
COVID-19:多组学方法来识别导致风险和不良结果恢复能力的分子机制
  • 批准号:
    10382290
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
COVID-19: Multi-Omics Approach to Identify Molecular Mechanisms Responsible for Risk and Resilience to Adverse Outcomes
COVID-19:多组学方法来识别导致风险和不良结果恢复能力的分子机制
  • 批准号:
    10154323
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The Production of Microparticles During RBC Storage and Their Impact on Endothelial Phenotype In-vitro and In-vivo
红细胞储存过程中微粒的产生及其对体内外内皮表型的影响
  • 批准号:
    9323550
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
The Production of Microparticles During RBC Storage and Their Impact on Endothelial Phenotype In-vitro and In-vivo
红细胞储存过程中微粒的产生及其对体内外内皮表型的影响
  • 批准号:
    9167980
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Modulation of Endothelial Cell Function by the Shear Stress-Responsive miR-155
剪切应力响应性 miR-155 对内皮细胞功能的调节
  • 批准号:
    8309223
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Modulation of Endothelial Cell Function by the Shear Stress-Responsive miR-155
剪切应力响应性 miR-155 对内皮细胞功能的调节
  • 批准号:
    8668133
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Modulation of Endothelial Cell Function by the Shear Stress-Responsive miR-155
剪切应力响应性 miR-155 对内皮细胞功能的调节
  • 批准号:
    8465266
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Modulation of Endothelial Cell Function by the Shear Stress-Responsive miR-155
剪切应力响应性 miR-155 对内皮细胞功能的调节
  • 批准号:
    8162633
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
The Impact of miR-21 Expression on Endothelial Cell Apoptosis and Inflammation
miR-21表达对内皮细胞凋亡和炎症的影响
  • 批准号:
    8196330
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
The Impact of miR-21 Expression on Endothelial Cell Apoptosis and Inflammation
miR-21表达对内皮细胞凋亡和炎症的影响
  • 批准号:
    7931520
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:

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