Shroom3 in nephron formation

Shroom3 在肾单位形成中的作用

基本信息

  • 批准号:
    RGPIN-2021-04289
  • 负责人:
  • 金额:
    $ 3.06万
  • 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:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

The long-term focus of my research program is to define the fundamental mechanisms of kidney development. Kidneys are composed of millions of nephrons that filter the blood and reabsorb ions, proteins, and water. This makes the nephron essential for homeostasis in virtually every multicellular organism. The proper development of the nephron is a fundamental requirement for proper nephron function. Nephron formation begins when loosely packed nephron progenitor mesenchyme (NPM) cells tightly cluster, alter their morphology, and transition to epithelia. Through extensive morphogenesis these structures progress through various stages to form the nephron. The correct clustering, organizing, and morphogenesis of the NPM cells is essential for setting the proper foundation for nephron function, yet little is known about the mechanisms regulating these processes. Shroom3 is an actin binding protein that regulates cell morphogenesis in developing epithelial such as the gut, eye, and neural tube. Despite the importance of cell morphogenesis for kidney development and significant evidence that Shroom3 is associated with poor kidney function, the fundamental mechanisms of Shroom3's actions in the kidney is lacking. Our published data demonstrates that adult Shroom3 mutant mice have poorly functioning nephrons composed of disorganized epithelia. Our unpublished data demonstrates that Shroom3 is 1) expressed in the NPM, 2) is required for NPM organization, 3) is required for clustering and renal vesicle formation. This data provides us with the opportunity to generate novel insights into the cellular morphogenetic mechanisms required for NPM cell clustering and patterning of the nephron. Using our newly generated Shroom3 conditional mouse model we will build on our exciting findings and dissect the cellular mechanisms by which Shroom3 regulates NPM aggregation and nephron formation. In this proposal we will contribute to our long-term goal by performing objective 1: Determine the effects of Shroom3 on the NPM cell morphology and the NPM transcriptome 2) Define the mechanisms by which shroom3 modulates nephron progenitor morphology and defining the Shroom3 protein interactome. The proposed plan will determine the contribution of Shroom3 in the regulation of nephron progenitor cell morphology, identify how morphological changes affect cellular communication, and identify up and down stream modulators of Shroom3. These studies will also extend our understanding of nephron progenitor formation and patterning during kidney development. Further, these studies will extend our understanding of Shroom3 mechanisms in cell and tissue morphogenesis and will contribute significant knowledge for future research. In addition, these studies will also provide further understanding as to why Shroom3 is associated with poor kidney function and address questions as to the most common cause of childhood kidney failure, which is abnormal kidney development.
我的研究计划的长期重点是确定肾脏发育的基本机制。肾脏由数百万个肾单位组成,这些肾单位过滤血液并重吸收离子、蛋白质和水。这使得肾单位对于几乎每一个多细胞生物体的体内平衡都是必不可少的。肾单位的正常发育是肾单位正常功能的基本要求。当松散堆积的肾单位祖细胞间充质(NPM)细胞紧密聚集,改变其形态并转变为上皮细胞时,肾单位形成开始。通过广泛的形态发生,这些结构通过不同的阶段发展形成肾单位。NPM细胞的正确聚集、组织和形态发生对于为肾单位功能奠定适当基础至关重要,但对调节这些过程的机制知之甚少。Shroom3是一种肌动蛋白结合蛋白,调节发育中的上皮细胞如肠道、眼睛和神经管的细胞形态发生。尽管细胞形态发生对肾脏发育的重要性以及Shroom3与肾功能差相关的重要证据,但Shroom3在肾脏中作用的基本机制仍然缺乏。我们发表的数据表明,成年Shroom3突变小鼠具有由紊乱的上皮细胞组成的功能不良的肾单位。我们未发表的数据表明Shroom3 1)在NPM中表达,2)是NPM组织所需的,3)是聚集和肾囊泡形成所需的。这些数据为我们提供了机会,以产生新的见解,细胞形态发生机制所需的NPM细胞群集和图案的肾单位。使用我们新生成的Shroom3条件小鼠模型,我们将建立在我们令人兴奋的发现和剖析Shroom3调节NPM聚集和肾单位形成的细胞机制。在本提案中,我们将通过执行目标1:确定Shroom3对NPM细胞形态和NPM转录组的影响来促进我们的长期目标。2)定义Shroom3调节肾单位祖细胞形态的机制并定义Shroom3蛋白相互作用组。拟议的计划将确定Shroom3在肾单位祖细胞形态调节中的贡献,确定形态变化如何影响细胞通讯,并确定Shroom3的上游和下游调节剂。这些研究也将扩展我们对肾脏发育过程中肾单位祖细胞形成和模式的理解。此外,这些研究将扩展我们对Shroom3在细胞和组织形态发生中的机制的理解,并将为未来的研究提供重要的知识。此外,这些研究还将进一步了解Shroom3与肾功能不良相关的原因,并解决儿童肾衰竭最常见的原因,即肾脏发育异常。

项目成果

期刊论文数量(0)
专著数量(0)
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Bridgewater, Darren其他文献

Developmental Origins for Kidney Disease Due to Shroom3 Deficiency
Stromally Expressed β-Catenin Modulates Wnt9b Signaling in the Ureteric Epithelium
  • DOI:
    10.1371/journal.pone.0120347
  • 发表时间:
    2015-03-24
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Boivin, Felix J.;Sarin, Sanjay;Bridgewater, Darren
  • 通讯作者:
    Bridgewater, Darren
BMP receptor ALK3 controls collecting system development
  • DOI:
    10.1681/asn.2007010080
  • 发表时间:
    2008-01-01
  • 期刊:
  • 影响因子:
    13.6
  • 作者:
    Hartwig, Sunny;Bridgewater, Darren;Rosenblum, Norman D.
  • 通讯作者:
    Rosenblum, Norman D.
Quercetin treatment reduces the severity of renal dysplasia in a beta-catenin dependent manner
  • DOI:
    10.1371/journal.pone.0234375
  • 发表时间:
    2020-06-17
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Cunanan, Joanna;Deacon, Erin;Bridgewater, Darren
  • 通讯作者:
    Bridgewater, Darren
Insights into the Renal Pathogenesis in Schimke Immuno-Osseous Dysplasia: A Renal Histological Characterization and Expression Analysis
  • DOI:
    10.1369/0022155414558335
  • 发表时间:
    2015-01-01
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    Sarin, Sanjay;Javidan, Ashkan;Bridgewater, Darren
  • 通讯作者:
    Bridgewater, Darren

Bridgewater, Darren的其他文献

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{{ truncateString('Bridgewater, Darren', 18)}}的其他基金

Shroom3 in nephron formation
Shroom3 在肾单位形成中的作用
  • 批准号:
    RGPIN-2021-04289
  • 财政年份:
    2021
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Regulation of Cell Signaling and Branching morphogenesis
细胞信号传导和分支形态发生的调节
  • 批准号:
    405644-2012
  • 财政年份:
    2017
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Regulation of Cell Signaling and Branching morphogenesis
细胞信号传导和分支形态发生的调节
  • 批准号:
    405644-2012
  • 财政年份:
    2015
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Regulation of Cell Signaling and Branching morphogenesis
细胞信号传导和分支形态发生的调节
  • 批准号:
    405644-2012
  • 财政年份:
    2014
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Regulation of Cell Signaling and Branching morphogenesis
细胞信号传导和分支形态发生的调节
  • 批准号:
    405644-2012
  • 财政年份:
    2013
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
Regulation of Cell Signaling and Branching morphogenesis
细胞信号传导和分支形态发生的调节
  • 批准号:
    405644-2012
  • 财政年份:
    2012
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
PGSB
PGSB
  • 批准号:
    254434-2002
  • 财政年份:
    2003
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Postgraduate Scholarships
PGSB
PGSB
  • 批准号:
    254434-2002
  • 财政年份:
    2002
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Postgraduate Scholarships

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    2023
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Epigenetic mechanisms of gene regulation in nephron progenitor cell proliferation and differentiation
肾单位祖细胞增殖和分化基因调控的表观遗传机制
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    2021
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Shroom3 in nephron formation
Shroom3 在肾单位形成中的作用
  • 批准号:
    RGPIN-2021-04289
  • 财政年份:
    2021
  • 资助金额:
    $ 3.06万
  • 项目类别:
    Discovery Grants Program - Individual
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肾单位祖细胞增殖和分化基因调控的表观遗传机制
  • 批准号:
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  • 财政年份:
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    $ 3.06万
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肾单位祖细胞增殖和分化基因调控的表观遗传机制
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  • 财政年份:
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    10063867
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    $ 3.06万
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Functional characterization of a novel key regulator of the distal nephron whose deficiency leads to renal fibrosis and cyst formation
远端肾单位新型关键调节因子的功能特征,其缺陷导致肾纤维化和囊肿形成
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    2018
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