Role of miRNAs in Vascular Physiology

miRNA 在血管生理学中的作用

基本信息

  • 批准号:
    8304423
  • 负责人:
  • 金额:
    $ 24.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle, leading to right ventricular failure. PAH is a serious condition for which there is no cure. Primary PAH is a rare but progressive disease with a mortality of 30 percent over 4 years. Recently germline mutations in bone morphogenetic protein receptor type II (BMPRII), a member of the transforming growth factor 2 (TGF2) receptor family, have been found in over 80 percent of familial PAH patients and in 30 percent of sporadic cases of PAH. The long-term objective of this application is to understand the molecular mechanism(s) by which BMPRII mutations contribute to the pathogenesis of PAH. The hypothesis of this application is that BMPR2 and its downstream signal are essential for maintenance of a normal pulmonary vascular structure and function. We have shown previously that the TGF2 family of growth factors, TGF2s and BMPs, promote a switch from a "synthetic" to "contractile" phenotype of pulmonary artery smooth muscle cells (PASMCs) by inducing the expression of VSMC-specific genes. We recently demonstrated that the expression of microRNA-21 (miR-21) is rapidly induced after a treatment with TGF2 or BMP in PASMCs. MiR-21 belongs to a family of short, noncoding, single-stranded RNAs (ssRNAs) called microRNAs (miRNAs) that regulate gene expression by targeting mRNAs in a sequence-specific manner, causing translational repression or mRNA degradation. Induction of miR-21 in PASMCs leads to downregulation of Programmed Cell Death 4 (PDCD4) which in turn leads to the elevation of VSMC-specific gene expression. Interestingly, our data indicate that TGF2 and BMP mediate miR-21 induction post- transcriptionally by promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR- 21 (pre-miR-21) by the Drosha microprocessor complex in the nucleus. The main goal of this application is to investigate a mechanism of regulation of miR-21 biosynthesis by TGF2 and BMP, which is crucial for understanding a molecular mechanism of TGF2/BMP-mediated phenotype switch underlying the pathogenesis of PAH. To this end, SA1 will examine a mechanism of association of Smads with specific pri-miRNAs. SA2 will elucidate a role of Smad proteins in the TGF2/BMP-regulated pri-miR-21 processing. SA3 will explore a role of miR-21 target PDCD4 in the regulation of vascular smooth muscle phenotype. This application investigates the previously unexplored mechanism of gene regulation by the TGF2/BMP-Smad signaling pathway which is fundamental for understanding the pathogenesis and development of novel therapies for PAH. PUBLIC HEALTH RELEVANCE: Vascular smooth muscle cells (VSMC) are characterized in part by their ability to modulate their phenotype between a quiescent, differentiated "contractile" state and a proliferative, less differentiated, "synthetic" state; further, upon vascular damage, VSMCs adopt the synthetic phenotype as part of a normal repair process. It is suggested that the phenotypic modulation of VSMCs contributes to various disorders in the pulmonary and systemic arteries, including post-angioplasty re-stenosis, transplant vasculopathy, atherosclerosis, lymphangioleiomyomatosis, and pulmonary arterial hypertension (PAH). This application will elucidate a novel mechanism of regulation of VSMC phenotype in normal physiology, which is of fundamental importance in understanding the etiology of cardiovascular disorders.
描述(由申请人提供):肺动脉高压(PAH)的特征是肺血管抗性增加,阻碍了右心室的血液射出,导致右心室衰竭。 PAH是一个严重的条件,无法治愈。原发性PAH是一种罕见但进行性疾病,在4年内死亡30%。最近在80%的家族性PAH患者和30%的零星PAH病例中发现了骨形态发生蛋白受体II型(BMPRII)(BMPRII)的种系突变。该应用的长期目标是了解BMPRII突变有助于PAH发病机理的分子机制。该应用的假设是BMPR2及其下游信号对于维持正常的肺血管结构和功能至关重要。我们先前已经表明,TGF2生长因子(TGF2和BMP)的TGF2家族通过诱导VSMC特异性基因的表达来促进从肺动脉平滑肌细胞(PASMC)的“合成”转换为“收缩”表型。我们最近证明,在PASMC中用TGF2或BMP处理后,microRNA-21(miR-21)的表达迅速诱导。 miR-21属于一个称为microRNA(miRNA)的短,非编码,单链RNA(SSRNA)的家族,该家族通过以序列特异性方式靶向mRNA来调节基因表达,从而导致翻译抑制或mRNA降解。 PASMC中miR-21的诱导导致程序性细胞死亡4(PDCD4)的下调,进而导致VSMC特异性基因表达的升高。有趣的是,我们的数据表明,TGF2和BMP在转录后通过促进了miR-21(PRI-MIR-21)的一级转录本在原子核中的Drosha微处理仪中介导MiR-21诱导。该应用的主要目的是研究TGF2和BMP调节miR-21生物合成的机制,这对于理解TGF2/BMP介导的表型的分子机制至关重要。PAH的发病机理。为此,SA1将检查SMAD与特定Pri-MiRNA的关联机理。 SA2将阐明SMAD蛋白在TGF2/BMP调节的PRI-MIR-21处理中的作用。 SA3将探讨miR-21靶PDCD4在调节血管平滑肌表型中的作用。该应用研究了TGF2/BMP-SMAD信号通路对基因调节的先前未开发的机制,这对于理解PAH的新疗法的发病机理和发育至关重要。 公共卫生相关性:血管平滑肌细胞(VSMC)的特征是它们在静止的,分化的“收缩”状态和增殖,较小的,差异化的“合成”状态之间调节其表型的能力;此外,在血管损伤后,VSMC采用合成表型作为正常修复过程的一部分。有人提出,VSMC的表型调节有助于肺动脉和全身动脉的各种疾病,包括血管成形术后再生术,移植血管性血管性,动脉粥样硬化,淋巴结杆菌病和肺动脉高血压(PAH)。该应用将阐明正常生理学中VSMC表型调节的新型机制,这对于理解心血管疾病的病因至关重要。

项目成果

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Akiko Hata其他文献

Akiko Hata的其他文献

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{{ truncateString('Akiko Hata', 18)}}的其他基金

Elucidating the structural insights into the BMP receptor mutations in PAH
阐明 PAH 中 BMP 受体突变的结构见解
  • 批准号:
    10659947
  • 财政年份:
    2023
  • 资助金额:
    $ 24.36万
  • 项目类别:
Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
  • 批准号:
    10211271
  • 财政年份:
    2021
  • 资助金额:
    $ 24.36万
  • 项目类别:
Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
  • 批准号:
    10400195
  • 财政年份:
    2021
  • 资助金额:
    $ 24.36万
  • 项目类别:
Molecular pathogenesis of pulmonary arterial hypertension
肺动脉高压的分子发病机制
  • 批准号:
    10560621
  • 财政年份:
    2021
  • 资助金额:
    $ 24.36万
  • 项目类别:
Identification of a novel modulator of Pulmonary Artery Hypertension
一种新型肺动脉高压调节剂的鉴定
  • 批准号:
    9282758
  • 财政年份:
    2016
  • 资助金额:
    $ 24.36万
  • 项目类别:
Identification of a novel modulator of Pulmonary Artery Hypertension
一种新型肺动脉高压调节剂的鉴定
  • 批准号:
    9088922
  • 财政年份:
    2016
  • 资助金额:
    $ 24.36万
  • 项目类别:
Role of the PDGF signaling pathway in pulmonary artery hypertension
PDGF信号通路在肺动脉高压中的作用
  • 批准号:
    8461453
  • 财政年份:
    2013
  • 资助金额:
    $ 24.36万
  • 项目类别:
Role of the PDGF signaling pathway in pulmonary artery hypertension
PDGF信号通路在肺动脉高压中的作用
  • 批准号:
    8714040
  • 财政年份:
    2013
  • 资助金额:
    $ 24.36万
  • 项目类别:
Role of miRNAs in Vascular Physiology
miRNA 在血管生理学中的作用
  • 批准号:
    8266380
  • 财政年份:
    2009
  • 资助金额:
    $ 24.36万
  • 项目类别:
Role of miRNAs in Vascular Physiology
miRNA 在血管生理学中的作用
  • 批准号:
    7653575
  • 财政年份:
    2009
  • 资助金额:
    $ 24.36万
  • 项目类别:

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