Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation

肾单位祖细胞自我更新和分化的调节

基本信息

  • 批准号:
    9258431
  • 负责人:
  • 金额:
    $ 12.83万
  • 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:
    2014-08-07 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of the proposed work is to determine how the Sall1 transcription factor and its associated chromatin remodeling complexes control gene regulation to generate a normal endowment of nephrons. This will illuminate mechanisms that underlie human genetic syndromes and common sporadic birth defects, such as renal hypoplasia (small kidneys with reduced numbers of nephrons), which result in kidney failure. Formation of the proper complement of nephrons requires a balance between expansion of multi-potent renal progenitor cells and differentiation. Genetic deficiency of Sall1 alters gene expression in the developing kidney, accelerating nephron differentiation leading to a depletion of nephron progenitor cells and renal hypoplasia. These uncommitted nephron precursors, termed cap mesenchyme, must respond to canonical Wnt/ß-catenin signals by either undergoing self-renewal or mesenchymal-to-epithelial transition to form most tubular segments of the nephron. The transcriptional mechanisms that control these opposing responses of the cap mesenchyme are not known, but current evidence argues that Sall1 is pivotal in this critical developmental decision. Our recent studies provide evidence for a novel paradigm. We propose that Sall1 cooperates with the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex, to determine nephron progenitor cell fate by regulating the transcriptional output in response to Wnt/ß-catenin. This application will test key predictions of this model using a combination of genetic, genomic, and biochemical approaches. Six2 is an inhibitor of nephron differentiation. In Aim 1, we will determine if Sall1 directly up-regulates Six2 expression in cap mesenchyme to restrain differentiation of progenitor cells. Expression of Wnt9b, the main differentiation signal, is increased in Sall1 mutants. We will determine if the combination of increased Wnt9b and reduced Six2 expression are sufficient to cause accelerated nephron formation, and exhaustion of self-renewing progenitor cells. Aim 2 will determine how Sall1 and NuRD control the transcriptional output in nephron progenitor cells to determine whether the uncommitted precursor cells undergo self-renewal or initiate nephron differentiation. The mechanistic insights gained from these studies will advance efforts to propagate nephron progenitors in vitro and/or promote regeneration of mature tubular epithelial cells in order to correct nephron deficits.
描述(由申请人提供):拟议工作的长期目标是确定Sall1转录因子及其相关的染色质重塑复合物如何控制基因调控以产生正常的肾单位。这将阐明人类遗传综合征和常见的散发性出生缺陷的机制,如肾发育不全(肾小,肾单位数量减少),导致肾衰竭。肾元适当补体的形成需要多能肾祖细胞的扩张和分化之间的平衡。Sall1基因缺失会改变发育中的肾脏的基因表达,加速肾元分化,导致肾元祖细胞耗竭和肾发育不全。这些未确定的肾细胞前体,称为帽间质,必须通过自我更新或间质到上皮的转变来响应典型的Wnt/ß-catenin信号,形成肾细胞的大多数小管段。控制帽间质这些相反反应的转录机制尚不清楚,但目前的证据表明,Sall1在这一关键的发育决定中起着关键作用。我们最近的研究为一种新的范式提供了证据。我们提出Sall1与核小体重塑和去乙酰化酶(NuRD)染色质重塑复合体合作,通过调节响应Wnt/ß-catenin的转录输出来决定肾元祖细胞的命运。这个应用程序将测试

项目成果

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MICHAEL I RAUCHMAN其他文献

MICHAEL I RAUCHMAN的其他文献

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{{ truncateString('MICHAEL I RAUCHMAN', 18)}}的其他基金

Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
  • 批准号:
    10530271
  • 财政年份:
    2022
  • 资助金额:
    $ 12.83万
  • 项目类别:
Research Project 2: Molecular analysis of developing post-natal mouse kidney in health and FSGS
研究项目2:健康和FSGS中小鼠产后肾脏发育的分子分析
  • 批准号:
    10707966
  • 财政年份:
    2022
  • 资助金额:
    $ 12.83万
  • 项目类别:
Single Cell Chromatin Profiling in Kidney Tissue
肾脏组织中的单细胞染色质分析
  • 批准号:
    10373426
  • 财政年份:
    2021
  • 资助金额:
    $ 12.83万
  • 项目类别:
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
  • 批准号:
    10289761
  • 财政年份:
    2021
  • 资助金额:
    $ 12.83万
  • 项目类别:
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
  • 批准号:
    10672271
  • 财政年份:
    2021
  • 资助金额:
    $ 12.83万
  • 项目类别:
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
  • 批准号:
    10442628
  • 财政年份:
    2021
  • 资助金额:
    $ 12.83万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    9607382
  • 财政年份:
    2018
  • 资助金额:
    $ 12.83万
  • 项目类别:
Mechanisms and Treatment of Kidney Fibrosis
肾脏纤维化的机制和治疗
  • 批准号:
    10660981
  • 财政年份:
    2018
  • 资助金额:
    $ 12.83万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    8638282
  • 财政年份:
    2014
  • 资助金额:
    $ 12.83万
  • 项目类别:
Regulation of Nephron Progenitor Cell Self-Renewal and Differentiation
肾单位祖细胞自我更新和分化的调节
  • 批准号:
    8908006
  • 财政年份:
    2014
  • 资助金额:
    $ 12.83万
  • 项目类别:

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