Regulation of vascular smooth muscle cell plasticity

血管平滑肌细胞可塑性的调节

基本信息

  • 批准号:
    8998052
  • 负责人:
  • 金额:
    $ 41.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-02-03 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Regulation of VSMC phenotype remains a key unanswered question in vascular smooth muscle cell (VSMC) biology. VSMC retain a remarkable plasticity to de-differentiate and re-enter the cell cycle allowing for growth and healing. However, such plasticity can also contribute to severe vascular pathologies, including restenosis, graft failure, atherosclerosis, and transplant vasculopathy. Remarkably, despite intense study, the process regulating VSMC plasticity is largely unknown with few therapies successfully targeting this process. With the growing numbers of patients suffering from vascular disease the discovery of novel targets is urgently warranted. We have made the exciting discovery that de-differentiated VSMC express genes associated with stem cell pluripotency, including Sox2, Oct4, Nanog, and KLF4. We propose that these stem cell-associated genes account for the unique plasticity of mature VSMC. Recent groundbreaking studies have identified the TET (ten-eleven translocations) family of chromatin modifying proteins as key mediators of pluripotency in embryonic and hematopoietic stem cells. Our Preliminary Results implicate TET2 as an epigenetic master regulator of VSMC phenotype. Importantly, we find that TET2 inhibits expression of stem cell-associated genes and classic markers of the de-differentiated phenotype. We previously discovered that the mTORC1 inhibitor, rapamycin, promotes VSMC differentiation. We now find that rapamycin regulates TET2 expression. Remarkably, we find that TET2 also regulates miRNAs that can modulate both differentiation-specific and stem cell-associated gene expression. We hypothesize that TET2 is a master regulator of VSMC phenotype through its coordinated regulation of the promoters of contractile and stem cell-associated genes, as well as of miRNAs. In Specific Aim 1, we will determine the role of stem cell-associated genes in VSMC phenotype. In Specific Aim 2, we will determine the role of TET2-regulated miRNAs in VSMC phenotype. In Specific Aim 3, we will determine whether targeting TET2 or stem cell-associated genes has therapeutic utility in in vivo models of intimal hyperplasia. If our goals are achieved, we will have identified a nove mechanism underlying VSMC plasticity. Understanding the critical mechanisms by which mTORC1 regulates VSMC phenotype will lead to improved cardiovascular therapeutics.
描述(由申请方提供):VSMC表型的调节仍然是血管平滑肌细胞(VSMC)生物学中一个关键的未回答的问题。VSMC保持显著的可塑性去分化并重新进入细胞周期,从而允许生长和愈合。然而,这种可塑性也可能导致严重的血管病变,包括再狭窄、移植失败、动脉粥样硬化和移植血管病变。值得注意的是,尽管进行了大量的研究,但调节VSMC可塑性的过程在很大程度上是未知的,很少有成功靶向该过程的疗法。随着越来越多的患者患有血管疾病,新的目标的发现是迫切需要的。 我们已经取得了令人兴奋的发现,去分化的VSMC表达与干细胞多能性相关的基因,包括Sox 2,Oct 4,Nanog和KLF 4。我们认为,这些干细胞相关基因占成熟VSMC的独特可塑性。最近的突破性研究已经鉴定了染色质修饰蛋白的泰特(10 - 11易位)家族作为胚胎和造血干细胞中多能性的关键介质。我们的初步结果暗示TET 2作为VSMC表型的表观遗传主调节因子。重要的是,我们发现TET 2抑制干细胞相关基因和去分化表型的经典标志物的表达。我们先前发现mTORC 1抑制剂雷帕霉素促进VSMC分化。我们现在发现雷帕霉素调节TET 2表达。值得注意的是,我们发现TET 2还调节可以调节分化特异性和干细胞相关基因表达的miRNA。我们假设TET 2是VSMC表型的主要调节因子,通过其协调调节收缩和干细胞相关基因的启动子以及miRNA。在具体目标1中,我们将确定干细胞相关基因在VSMC表型中的作用。在具体目标2中,我们将确定TET 2调节的miRNA在VSMC表型中的作用。在具体目标3中,我们将确定靶向TET 2或干细胞相关基因是否在内膜增生的体内模型中具有治疗效用。如果我们的目标得以实现,我们将发现一种新的VSMC可塑性机制。了解mTORC 1调节VSMC表型的关键机制将有助于改善心血管治疗。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Kathleen Ann Martin其他文献

Kathleen Ann Martin的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Kathleen Ann Martin', 18)}}的其他基金

Vascular Discovery, From Genes to Medicine 2023
血管发现,从基因到医学 2023
  • 批准号:
    10683501
  • 财政年份:
    2023
  • 资助金额:
    $ 41.63万
  • 项目类别:
2022 Vascular Discovery: From Genes to Medicine
2022 年血管发现:从基因到医学
  • 批准号:
    10469131
  • 财政年份:
    2022
  • 资助金额:
    $ 41.63万
  • 项目类别:
Role of LMO7 in atherosclerosis
LMO7 在动脉粥样硬化中的作用
  • 批准号:
    10453451
  • 财政年份:
    2020
  • 资助金额:
    $ 41.63万
  • 项目类别:
Role of LMO7 in atherosclerosis
LMO7 在动脉粥样硬化中的作用
  • 批准号:
    10224324
  • 财政年份:
    2020
  • 资助金额:
    $ 41.63万
  • 项目类别:
Role of LMO7 in atherosclerosis
LMO7 在动脉粥样硬化中的作用
  • 批准号:
    10670757
  • 财政年份:
    2020
  • 资助金额:
    $ 41.63万
  • 项目类别:
Novel insights into intimal hyperplasia in cardiac allograft vasculopathy
对心脏同种异体移植血管病中内膜增生的新见解
  • 批准号:
    10090623
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Epigenetic control of vascular smooth muscle in cardiovascular disease
心血管疾病中血管平滑肌的表观遗传控制
  • 批准号:
    8761918
  • 财政年份:
    2014
  • 资助金额:
    $ 41.63万
  • 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
  • 批准号:
    8630004
  • 财政年份:
    2014
  • 资助金额:
    $ 41.63万
  • 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
  • 批准号:
    8798690
  • 财政年份:
    2014
  • 资助金额:
    $ 41.63万
  • 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
  • 批准号:
    9211370
  • 财政年份:
    2014
  • 资助金额:
    $ 41.63万
  • 项目类别:

相似海外基金

Development of a balloon angioplasty catheter capable of simultaneous endovascular delivery of liquid therapeutic agents into the vascular wall
开发能够同时将液体治疗剂血管内输送到血管壁的球囊血管成形术导管
  • 批准号:
    10324960
  • 财政年份:
    2021
  • 资助金额:
    $ 41.63万
  • 项目类别:
Simplified Transfemoral Carotid Angioplasty and Stenting Under FlowReversal Using a Novel Combination Access Sheath/Balloon System
使用新型组合通路鞘/球囊系统在血流逆转下简化经股颈动脉血管成形术和支架置入术
  • 批准号:
    10081007
  • 财政年份:
    2020
  • 资助金额:
    $ 41.63万
  • 项目类别:
Balloon Angioplasty Inflation Device
球囊血管成形术充气装置
  • 批准号:
    10019316
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
Elucidation of appropriate patients for percutaneous transluminal renal angioplasty treatment
阐明适合经皮腔内肾血管成形术治疗的患者
  • 批准号:
    17K09743
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of a Novel Angioplasty Catheter for Treatment of Calcified Arteries
开发用于治疗钙化动脉的新型血管成形术导管
  • 批准号:
    MR/P026850/1
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Research Grant
Balloon Angioplasty Inflation Device
球囊血管成形术充气装置
  • 批准号:
    9410026
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
A Preclinical Trial of Therapeutic Angiogenesis Plus Angioplasty and Stenting for Renal Vascular Disease
治疗性血管生成加血管成形术和支架置入术治疗肾血管疾病的临床前试验
  • 批准号:
    9249339
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
Basic research about application of liposomes to prevent stenosis after angioplasty of craniocervical artery stenosis
应用脂质体预防颅颈动脉狭窄血管成形术后狭窄的基础研究
  • 批准号:
    25462205
  • 财政年份:
    2013
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Utility Of Adenosine Stress Cardiac Magnetic Resonance Imaging Following ST Elevation Myocardial Infarction Post Primary Angioplasty
ST 段抬高型心肌梗死初次血管成形术后腺苷应激心脏磁共振成像的效用
  • 批准号:
    nhmrc : 1018161
  • 财政年份:
    2011
  • 资助金额:
    $ 41.63万
  • 项目类别:
    NHMRC Postgraduate Scholarships
Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty
治疗球囊血管成形术后血管损伤的新方法
  • 批准号:
    8402612
  • 财政年份:
    2011
  • 资助金额:
    $ 41.63万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了