PTEN-dependent regulation of SRF transcriptional activity and SMC phenotype control

SRF 转录活性的 PTEN 依赖性调节和 SMC 表型控制

基本信息

  • 批准号:
    9247031
  • 负责人:
  • 金额:
    $ 49.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-05 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): A unique characteristic of resident vascular smooth muscle cells (SMCs) and a hallmark of vascular disease progression is SMC phenotypic switching marked by a change in SMC phenotype. Regulation of PTEN, a lipid and protein phosphatase that predominantly inhibits cytoplasmic PI3K/Akt activity, is critical in pathological vascular remodeling. PTEN represses SMC phenotypic switching while its loss results in decreased SM contractile gene expression and increased proliferation and production inflammatory mediators. Enhanced proliferation and inflammatory mediator production are dependent on loss of PTEN's phosphatase activity and consequent increased Akt activity. However, since SM genes are under direct transcriptional control by serum response factor (SRF), the mechanism underlying PTEN's regulation of SM gene expression remained unclear and is the focus of this proposal. Under physiological conditions, SMCs express a quiescent, differentiated phenotype, characterized by high expression of SRF-dependent SM genes. SRF is a ubiquitous and essential transcription factor that binds CArG elements in SM genes. Paradoxically, SRF also regulates immediate early genes. Control of SM gene expression by SRF involves interactions between SRF and cell-specific co- activators, epigenetic control of gene expression, and regulation of SRF through post-translational modifications and spatial/temporal changes. Our new published and preliminary data show a direct link between PTEN and SRF in this regulation. Our published studies demonstrated that PTEN is a downstream effector of SRF through a microRNA (miRNA)-dependent pathway. Loss of this axis promotes reprogramming to a proliferative, inflammatory phenotype. To support this current project, new preliminary data suggest a novel upstream function for nuclear PTEN that is independent of its phosphatase activity. We demonstrate direct interaction of PTEN with SRF, which facilitates SRF-dependent SM gene transcription suggesting a positive feedback loop involving PTEN and SRF. Pathophysiologic or genetic loss of PTEN results in loss of SRF binding to SM gene promoters and SMC phenotypic switching. Clinically, loss of nuclear PTEN and overall decreased expression is observed in intimal SMCs of human atherosclerotic lesions, supporting a critical role for nuclear PTEN in regulation of lesion progression. We propose a positive feedback loop between PTEN and SRF underlies maintenance of a differentiated, quiescent SMC phenotype. We hypothesize that physiologic or pathologic stimuli induce nuclear exclusion of PTEN and SRF with subsequent inhibition of SRF- dependent SM gene transcription and dysregulation of the SRF-miRNA-PTEN network controlling proliferation and inflammation. We will define the molecular mechanisms underlying PTEN regulation of SRF transcriptional activity (Aim One), establish the importance of PTEN-dependent regulation of SRF transcriptional activity using complex genetic mouse models of atherosclerosis and vascular injury (Aim Two), and establish the significance of nuclear PTEN on SMC phenotype in normal and diseased human arteries (Aim Three).
 描述(由申请方提供):固有血管平滑肌细胞(SMC)的一个独特特征和血管疾病进展的标志是SMC表型转换,其特征为SMC表型变化。PTEN是一种主要抑制细胞质PI 3 K/Akt活性的脂质和蛋白磷酸酶,其调节在病理性血管重塑中至关重要。PTEN抑制SMC表型转换,而其缺失导致SM收缩基因表达降低,增殖和炎症介质产生增加。增强的增殖和炎性介质产生依赖于PTEN磷酸酶活性的丧失和随之增加的Akt活性。然而,由于SM基因是在血清反应因子(SRF)的直接转录控制下,潜在的机制PTEN的调节SM基因的表达仍然不清楚,是这个建议的焦点。在生理条件下,SMC表达静止的分化表型,其特征在于SRF依赖性SM基因的高表达。SRF是SM基因中普遍存在的必需转录因子,它与CArG元件结合。巧合的是,SRF也调节即刻早期基因。SRF对SM基因表达的控制涉及SRF与细胞特异性共激活因子之间的相互作用、基因表达的表观遗传控制以及通过翻译后修饰和空间/时间变化对SRF的调节。我们新发表的和初步的数据显示,在这种调节中,PTEN和SRF之间存在直接联系。我们已发表的研究表明,PTEN是通过microRNA(miRNA)依赖性途径的SRF的下游效应子。该轴的丢失促进重编程为增殖性、炎性表型。为了支持目前的项目,新的初步数据表明,一个新的上游功能的核PTEN是独立的磷酸酶活性。我们证明了PTEN与SRF的直接相互作用,这有利于SRF依赖的SM基因转录,这表明涉及PTEN和SRF的正反馈回路。PTEN的病理生理或遗传缺失导致SRF与SM基因启动子结合的缺失和SMC表型转换。临床上,在人动脉粥样硬化病变的内膜SMC中观察到核PTEN的丢失和总体表达降低,支持核PTEN在调节病变进展中的关键作用。我们提出了一个正反馈环之间的PTEN和SRF维持分化,静止SMC表型的基础。我们假设生理或病理刺激诱导PTEN和SRF的核排斥,随后抑制SRF依赖性SM基因转录和控制增殖和炎症的SRF-miRNA-PTEN网络的失调。我们将确定潜在的SRF转录活性的PTEN调控的分子机制(目的一),建立的SRF转录活性的PTEN依赖性调节的重要性,使用复杂的遗传小鼠模型的动脉粥样硬化和血管损伤(目的二),并建立正常和患病的人动脉SMC表型的核PTEN的意义(目的三)。

项目成果

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Mary Cm. Weiser-Evans其他文献

Mary Cm. Weiser-Evans的其他文献

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{{ truncateString('Mary Cm. Weiser-Evans', 18)}}的其他基金

PTEN promoter hypermethylation underlies vascular disease progression
PTEN 启动子高甲基化是血管疾病进展的基础
  • 批准号:
    10330591
  • 财政年份:
    2021
  • 资助金额:
    $ 49.55万
  • 项目类别:
PTEN promoter hypermethylation underlies vascular disease progression
PTEN 启动子高甲基化是血管疾病进展的基础
  • 批准号:
    10543851
  • 财政年份:
    2021
  • 资助金额:
    $ 49.55万
  • 项目类别:
Reprogramming of mature smooth muscle cells to vascular progenitor cells
成熟平滑肌细胞重编程为血管祖细胞
  • 批准号:
    8967222
  • 财政年份:
    2014
  • 资助金额:
    $ 49.55万
  • 项目类别:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
分化平滑肌细胞的微环境内源性重编程
  • 批准号:
    8451768
  • 财政年份:
    2013
  • 资助金额:
    $ 49.55万
  • 项目类别:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
分化平滑肌细胞的微环境内源性重编程
  • 批准号:
    8666806
  • 财政年份:
    2013
  • 资助金额:
    $ 49.55万
  • 项目类别:
Role of PTEN in Vascular Lesion Formation
PTEN 在血管病变形成中的作用
  • 批准号:
    8011968
  • 财政年份:
    2009
  • 资助金额:
    $ 49.55万
  • 项目类别:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
PTEN 在缺氧诱导的血管重塑中的作用,Raphael Nemenoff
  • 批准号:
    7662790
  • 财政年份:
    2009
  • 资助金额:
    $ 49.55万
  • 项目类别:
Role of PTEN in Vascular Lesion Formation
PTEN 在血管病变形成中的作用
  • 批准号:
    7580629
  • 财政年份:
    2009
  • 资助金额:
    $ 49.55万
  • 项目类别:
Role of PTEN in Vascular Lesion Formation
PTEN 在血管病变形成中的作用
  • 批准号:
    7754395
  • 财政年份:
    2009
  • 资助金额:
    $ 49.55万
  • 项目类别:
Role of PTEN in Vascular Lesion Formation
PTEN 在血管病变形成中的作用
  • 批准号:
    8207875
  • 财政年份:
    2009
  • 资助金额:
    $ 49.55万
  • 项目类别:

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