Novel roles of RNA modifications in the pathogenesis of pulmonary vascular remodeling and PAH

RNA修饰在肺血管重塑和PAH发病机制中的新作用

基本信息

  • 批准号:
    10540134
  • 负责人:
  • 金额:
    $ 68万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and obliterative vascular remodeling that causes right heart failure and premature death. Given the underlying molecular mechanisms of obliterative vascular remodeling remain enigmatic, current therapies have not targeted the fundamental disease modifying mechanisms and hence only resulted in a modest improvement in the morbidity and mortality. While several transcription factors and transcriptional co- activators have been studied in the context of PAH, post-transcriptional regulations of mRNAs that can affect expression of key proteins remain largely unexplored. RNA modifications including N6-methyladenosine (m6A) have recently been discovered as essential regulators of gene expression. The m6A modification controls RNA stability, transport, and translation and has been linked to human diseases such as obesity and cancers. Despite its functional importance in various fundamental bioprocesses, studies of m6A modification of mRNAs in PAH are lacking. Our Supporting Data show that expression of fat mass and obesity-associated protein (FTO), a well-characterized RNA demethylase, is markedly elevated in pulmonary vascular endothelial cells (ECs) of idiopathic PAH patients. Tie2Cre-mediated deletion of Fto in ECs (FtoTie2Cre) inhibited PH induced by chronic hypoxia. Our mechanistic studies provide evidence that several PAH-causing genes are potential FTO targets in human lung ECs. Furthermore, pharmacological inhibition of FTO in monocrotaline- challenged rats inhibited pulmonary vascular remodeling and PH. Thus, we hypothesize that endothelial FTO, as a major m6A eraser, acts as a key regulator of mRNA stability and accumulation of key PAH-causing genes in ECs to regulate pulmonary vasoconstriction and vascular remodeling and thus is a novel therapeutic target for PAH. We propose the following 3 Specific Aims. In Aim 1, we will define the fundamental role of endothelial FTO in the pathogenesis of PAH. In Aim 2, we will delineate the molecular mechanisms underlying FTO regulation of endothelial dysfunction leading to pulmonary vasoconstriction and vascular remodeling. We will identify the key FTO targets in ECs and address the possibility of rescuing the phenotype of FtoTieCre by novel nanoparticle-mediated in vivo EC-specific gene transfer. In Aim 3, we will explore the therapeutic potential of FTO inhibitors including a repurposed FDA-approved drug in the treatment of PAH employing 3 complimentary animal models of PAH. Based on the clear clinical relevance of our novel findings, we expect that the proposed studies have significant translational potential by delineating the molecular and cellular mechanisms of endothelial dysfunction leading to pulmonary vasoconstriction and vascular remodeling, identifying druggable targets, and exploring pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling and also inhibit vasoconstriction for the prevention and treatment of PAH in patients. Thus, we believe the proposed studies have great translational potential.
肺动脉高压(PAH)以肺血管进行性增高为特征

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)

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YOU-YANG ZHAO其他文献

YOU-YANG ZHAO的其他文献

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{{ truncateString('YOU-YANG ZHAO', 18)}}的其他基金

Negative regulators of endothelial regeneration in aging lungs and ARDS
衰老肺和 ARDS 中内皮再生的负调节因子
  • 批准号:
    10467781
  • 财政年份:
    2022
  • 资助金额:
    $ 68万
  • 项目类别:
Negative regulators of endothelial regeneration in aging lungs and ARDS
衰老肺和 ARDS 中内皮再生的负调节因子
  • 批准号:
    10629328
  • 财政年份:
    2022
  • 资助金额:
    $ 68万
  • 项目类别:
Novel mechanisms of endothelial Injury in the pathogenesis of ARDS
ARDS发病机制中内皮损伤的新机制
  • 批准号:
    10434658
  • 财政年份:
    2020
  • 资助金额:
    $ 68万
  • 项目类别:
Novel mechanisms of endothelial Injury in the pathogenesis of ARDS
ARDS发病机制中内皮损伤的新机制
  • 批准号:
    10618326
  • 财政年份:
    2020
  • 资助金额:
    $ 68万
  • 项目类别:
Targeting Smooth Muscle Progenitor Cells for Treatment of Pulmonary Arterial Hypertension
靶向平滑肌祖细胞治疗肺动脉高压
  • 批准号:
    10189689
  • 财政年份:
    2018
  • 资助金额:
    $ 68万
  • 项目类别:
Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension
闭塞性肺血管重塑和严重肺动脉高压的新机制
  • 批准号:
    10470871
  • 财政年份:
    2016
  • 资助金额:
    $ 68万
  • 项目类别:
Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension
闭塞性肺血管重塑和严重肺动脉高压的新机制
  • 批准号:
    10316765
  • 财政年份:
    2016
  • 资助金额:
    $ 68万
  • 项目类别:
Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension
闭塞性肺血管重塑和严重肺动脉高压的新机制
  • 批准号:
    10677597
  • 财政年份:
    2016
  • 资助金额:
    $ 68万
  • 项目类别:
Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung
衰老肺内皮再生的新信号传导和分子靶点
  • 批准号:
    8909182
  • 财政年份:
    2014
  • 资助金额:
    $ 68万
  • 项目类别:
Novel Signalings and Molecular Targets of Endothelial Regeneration in Aging Lung
衰老肺内皮再生的新信号传导和分子靶点
  • 批准号:
    9307973
  • 财政年份:
    2014
  • 资助金额:
    $ 68万
  • 项目类别:

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