Role of Smooth Muscle Calponin in Vascular Pathobiology

平滑肌钙调蛋白在血管病理学中的作用

基本信息

  • 批准号:
    10077575
  • 负责人:
  • 金额:
    $ 56.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-11-07 至 2022-10-31
  • 项目状态:
    已结题

项目摘要

There is now incontrovertible evidence from sophisticated lineage tracing studies that vascular smooth muscle cell (VSMC) de-differentiation contributes substantively to a number of vascular diseases. A major manifesta- tion of such phenotypic change is attenuated expression of a battery of VSMC-restricted genes, including the enigmatic smooth muscle calponin (Cnn1) gene. The function of Cnn1 has been studied primarily in vitro or in a single knockout mouse wherein several exons and introns were replaced with a neo cassette which, as detailed below, obfuscates accurate interpretation of phenotypes. We have championed the CRISPR-Cas9 genome editing system in mice to engineer subtle substitutions within regulatory elements of many genes, leaving intact all coding sequences. We report here a remarkable phenotype wherein a single base change of a single CArG box in the Cnn1 locus abolishes expression of CNN1 in vascular (but not visceral) SMC. Full expression of CNN1 is restored with a BAC carrying human CNN1 or CRISPR-mediated activation of the en- dogenous Cnn1 promoter. Cnn1 CArG mutant mice, representing the first animal models of regulatory element edits, also show elevation in VSMC DNA synthesis and defective contractile competence. Conversely, over- expression of BAC-CNN1 suppresses VSMC growth, antagonizes neointimal formation, reduces VSMC lipid uptake, and enhances contractile gene expression. Interestingly, CNN1-Ser175 appears to be a critical residue for some of these effects making it an attractive amino acid for CRISPR-mediated editing in mice. Additional data support CNN1 as a scaffold for ERK signaling and effector of the immotile state of differentiated VSMC. Importantly, a complete understanding of CNN1 function is complicated by robust expression of two related genes (Cnn2 and Cnn3) in VSMC. We hypothesize that CNN1 functions in concert with other CNN isoforms to maintain a mature VSMC differentiated state. This hypothesis will be tested in three aims using state-of-the-art tools in genetics, animal models of disease, and molecular physiology assays of VSMC function. Aim 1 will exploit the single base edit in Cnn1 as a novel loss-of-function mouse in context of acute and chronic vascular disease models; complementation studies will be carried out in vitro and in vivo to rigorously ascribe pheno- typic changes to the specific loss of CNN1. Aim 2 will exploit a well-characterized BAC mouse to elucidate functions associated with Cnn1 gain-of-function in models of vascular disease used in Aim 1. Complementary CRISPR editing of the BAC mouse, in background of Cnn1 KO, will afford exquisite insight into functional residues that mediate CNN1 function. Aim 3 will exploit new floxed Cnn2 and Cnn3 mice with an exciting VSMC-specific Cre driver we have developed to address, for the first time, triple Cnn KO mouse models at baseline and in acute or chronic vascular disease models. These studies, based on paradigm-shifting approaches to gene KOs, serve as a template for the study of other gene families linked to VSMC differen- tiation and will inform future studies targeting CNN1 in diseases where VSMC differentiation is compromised.
现在有无可争议的证据来自复杂的谱系追踪研究血管平滑肌

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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Joseph M Miano其他文献

Joseph M Miano的其他文献

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{{ truncateString('Joseph M Miano', 18)}}的其他基金

Regulation and Function of SRF in Vascular Pathiobiology
SRF 在血管病理生物学中的调节和功能
  • 批准号:
    10337251
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Role of Smooth Muscle Calponin in Vascular Pathobiology
平滑肌钙调蛋白在血管病理学中的作用
  • 批准号:
    10053587
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Transcriptional Control of Myocardin and the MYOCARDome
心肌素和 MYOCARDome 的转录控制
  • 批准号:
    10210425
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Transcriptional Control of Myocardin and the MYOCARDome
心肌素和 MYOCARDome 的转录控制
  • 批准号:
    10059023
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Regulation and Function of SRF in Vascular Pathiobiology
SRF 在血管病理生物学中的调节和功能
  • 批准号:
    9764180
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Role of Smooth Muscle Calponin in Vascular Pathobiology
平滑肌钙调蛋白在血管病理学中的作用
  • 批准号:
    10308708
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Regulation and Function of SRF in Vascular Pathiobiology
SRF 在血管病理生物学中的调节和功能
  • 批准号:
    10060485
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Regulation and Function of SRF in Vascular Pathiobiology
SRF 在血管病理生物学中的调节和功能
  • 批准号:
    10112303
  • 财政年份:
    2019
  • 资助金额:
    $ 56.04万
  • 项目类别:
Regulation and Function of Myocardin in Vascular Pathobiology
心肌素在血管病理学中的调控和功能
  • 批准号:
    9042030
  • 财政年份:
    2013
  • 资助金额:
    $ 56.04万
  • 项目类别:
Regulation and Function of Myocardin in Vascular Pathobiology
心肌素在血管病理学中的调控和功能
  • 批准号:
    8820129
  • 财政年份:
    2013
  • 资助金额:
    $ 56.04万
  • 项目类别:

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