MicroRNA modulation of smooth muscle cell differentiation

MicroRNA 调节平滑肌细胞分化

基本信息

  • 批准号:
    RGPIN-2014-06360
  • 负责人:
  • 金额:
    $ 3.42万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2017
  • 资助国家:
    加拿大
  • 起止时间:
    2017-01-01 至 2018-12-31
  • 项目状态:
    已结题

项目摘要

Vascular smooth muscle cells (vSMCs) support blood vessels, and are integral for their ability to contract and be stabilized from hemorrhage. We are interested in the molecular control of differentiation of vascular smooth muscle. Given the outstanding ability to undertake genetic studies in zebrafish, we have developed a program to study smooth muscle development at the genetic and cellular levels. MicroRNAs (miRs) are short RNA sequences that control gene expression by targeting mRNA for translational repression or degradation. miR control of gene expression is rapidly reversible or ‘tunable’, rather than a simple on-off switch. This is interesting, as SMCs are one of the few cell types in our body that are not terminally differentiated and can switch phenotypes from being contractile to synthetic. Using the zebrafish model we have taken the first in vivo studies of mir26 function to show that knockdown of mir26 results in hemorrhage in vivo, poor smooth muscle-endothelial cell contacts, and SMC differentiation defects. The goal of our proposed research program is to understand how blood vessels are stabilized with the focus on mir26 and its downstream targets. Our general hypothesis is that a small group of critical mRNA targets are controlled in parallel by mir26 leading to smooth muscle cell differentiation and vascular stabilityHypothesis 1: mir26 controls SMC differentiation by controlling TGFß signalling via smad1 In this aim we will first test a known mir26 target for its role in vSMC development. We will use in vitro and in vivo assays to validate that smad1 is a direct target of miR26. We will also determine the morphological consequences of elevated smad1 during embryogenesis on SMC differentiation using microscopy and molecular markers. This aim describes an experimental 'pipeline' strategy that can be used to characterize additional targets.Hypothesis 2: Multiple RNAs important for modulation of SMC differentiation are targeted by miR26In this aim we data-mine published datasets from PAR-CLIP sequencing, a technique that sequences mRNAs that are microRNA associated to identify targets. From a list of mir26 targets generated by this technique in cancer cell lines, we will use expression screening to identify additional genes potentially regulated by mir26 during SMC differentiation in vivo in zebrafish. These targets will then be studied using the experimental strategy outlined in Aim 1. Our first two targets include the peptide hormone adrenomedullin and the TGFß pathway member ski. Hypothesis 3: Genes controlled by miR26 will work in parallel to promote SMC differentiation Aims 1 and 2 will identify multiple genes regulated by miR26, and we hypothesize that some will act in genetic pathways, while some will act in parallel. In this aim we will explore the genetic network regulated by miR26 using classical pathway analysis.Hypothesis 4: Delivery of miR26 in vivo to SMCs will modulate their genetic programOur ultimate goal is to understand whether miR26 can be used therapeutically. Since SMCs are thin cells directly adjacent to the endothelial lining, we hypothesize that administration of a miR in the circulation by angiography will result in the miR being taken up into SMCs. We will identify the localization and uptake of labelled miR26 and whether it has a phenotypic effect on SMC development.Significance: Our proposed program will identify a group of direct mir26 targets in SMCs in vivo. Nucleic acid based pharmaceuticals are theoretically inexpensive, stable and easy to administer. Therefore inhibition or augmentation of miR levels could be a feasible therapeutic strategy. In order to assess potential side-effects we are contributing to this field by identifying targets of miR26.
血管平滑肌细胞(vSMCs)支持血管,并为其收缩和稳定出血的能力是不可或缺的。我们对血管平滑肌分化的分子调控感兴趣。鉴于在斑马鱼中进行遗传研究的杰出能力,我们已经制定了一个在遗传和细胞水平上研究平滑肌发育的计划。MicroRNAs (miRs)是通过靶向mRNA进行翻译抑制或降解来控制基因表达的短RNA序列。miR对基因表达的控制是快速可逆的或“可调的”,而不是一个简单的开关。这很有趣,因为SMCs是我们身体中为数不多的未最终分化的细胞类型之一,可以将表型从收缩型转换为合成型。利用斑马鱼模型,我们首次在体内研究了mir26的功能,表明mir26的敲低会导致体内出血、平滑肌内皮细胞接触不良和SMC分化缺陷。我们提出的研究计划的目标是了解血管是如何稳定的,重点是mir26及其下游靶点。假设1:mir26通过通过smad1控制TGFß信号传导来控制SMC分化。为此,我们将首先测试一个已知的mir26靶点在vSMC发育中的作用。我们将使用体外和体内实验来验证smad1是miR26的直接靶点。我们还将利用显微镜和分子标记确定胚胎发生过程中smad1升高对SMC分化的形态学影响。该目标描述了一种实验性的“管道”策略,可用于表征其他目标。假设2:mir26靶向对SMC分化调制重要的多个rna。为此,我们对PAR-CLIP测序的公开数据集进行了数据挖掘,PAR-CLIP测序是一种对与microRNA相关的mrna进行测序以识别靶标的技术。从该技术在癌细胞系中产生的mir26靶点列表中,我们将使用表达筛选来鉴定斑马鱼体内SMC分化过程中mir26可能调控的其他基因。然后将使用Aim 1中概述的实验策略对这些目标进行研究。我们的前两个目标包括肽激素肾上腺髓质素和TGFß通路成员ski。假设3:受miR26控制的基因将平行作用以促进SMC分化。Aims 1和2将鉴定受miR26调控的多个基因,我们假设其中一些将在遗传途径中起作用,而另一些将平行作用。在这个目的中,我们将使用经典途径分析来探索miR26调控的遗传网络。假设4:体内将miR26递送至SMCs将调节其遗传程序。我们的最终目标是了解miR26是否可用于治疗。由于SMCs是直接与内皮细胞相邻的薄细胞,我们假设通过血管造影在循环中给药miR会导致miR被SMCs吸收。我们将确定标记miR26的定位和摄取,以及它是否对SMC的发展有表型影响。意义:我们提出的项目将在体内SMCs中确定一组直接的mir26靶点。从理论上讲,基于核酸的药物价格低廉、稳定且易于管理。因此,抑制或增加miR水平可能是一种可行的治疗策略。为了评估潜在的副作用,我们正在通过确定miR26的靶标为这一领域做出贡献。

项目成果

期刊论文数量(0)
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Childs, Sarah其他文献

MAPping out arteries and veins.
Critical mass theory and women's political representation
  • DOI:
    10.1111/j.1467-9248.2007.00712.x
  • 发表时间:
    2008-10-01
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Childs, Sarah;Krook, Mona Lena
  • 通讯作者:
    Krook, Mona Lena
"Quicker than a consultation at the hairdressers": abortion and the Human Fertilisation and Embryology Act 2008
  • DOI:
    10.1080/14636778.2013.788353
  • 发表时间:
    2013-06-01
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    Childs, Sarah;Evans, Elizabeth;Webb, Paul
  • 通讯作者:
    Webb, Paul

Childs, Sarah的其他文献

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{{ truncateString('Childs, Sarah', 18)}}的其他基金

Mechanisms of embryonic vascular mural cell differentiation and the onset of blood flow regulation
胚胎血管壁细胞分化的机制和血流调节的开始
  • 批准号:
    RGPIN-2019-07176
  • 财政年份:
    2022
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of embryonic vascular mural cell differentiation and the onset of blood flow regulation
胚胎血管壁细胞分化的机制和血流调节的开始
  • 批准号:
    RGPIN-2019-07176
  • 财政年份:
    2021
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of embryonic vascular mural cell differentiation and the onset of blood flow regulation
胚胎血管壁细胞分化的机制和血流调节的开始
  • 批准号:
    RGPIN-2019-07176
  • 财政年份:
    2020
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of embryonic vascular mural cell differentiation and the onset of blood flow regulation
胚胎血管壁细胞分化的机制和血流调节的开始
  • 批准号:
    RGPIN-2019-07176
  • 财政年份:
    2019
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA modulation of smooth muscle cell differentiation
MicroRNA 调节平滑肌细胞分化
  • 批准号:
    RGPIN-2014-06360
  • 财政年份:
    2018
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA modulation of smooth muscle cell differentiation
MicroRNA 调节平滑肌细胞分化
  • 批准号:
    RGPIN-2014-06360
  • 财政年份:
    2016
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA modulation of smooth muscle cell differentiation
MicroRNA调节平滑肌细胞分化
  • 批准号:
    RGPIN-2014-06360
  • 财政年份:
    2015
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA modulation of smooth muscle cell differentiation
MicroRNA调节平滑肌细胞分化
  • 批准号:
    RGPIN-2014-06360
  • 财政年份:
    2014
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA regulation of smooth muscle development
MicroRNA 调节平滑肌发育
  • 批准号:
    312496-2009
  • 财政年份:
    2011
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual
MicroRNA regulation of smooth muscle development
MicroRNA 调节平滑肌发育
  • 批准号:
    312496-2009
  • 财政年份:
    2010
  • 资助金额:
    $ 3.42万
  • 项目类别:
    Discovery Grants Program - Individual

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