Wnt/Frizzled-PCP signaling in development and disease

发育和疾病中的 Wnt/Frizzled-PCP 信号传导

基本信息

  • 批准号:
    9912774
  • 负责人:
  • 金额:
    $ 60.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-05-01 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis within the epithelial plane, referred to as Planar Cell Polarity (PCP). Cell polarity and ordered cellular patterning during organ development and homeostasis depend on PCP mechanisms. Classical PCP examples include in Drosophila adult cuticular structures. Similarly, in mammals striking aspects of PCP are evident in the skin, the inner ear epithelium, or the respiratory system and most other internal organs. Moreover, convergent extension processes during gastrulation and neural tube closure requires PCP signaling, and the PCP pathway is linked to the regulation of asymmetric cell divisions in stem cells of many organs. Studies of PCP establishment in Drosophila serve as a paradigm to unravel this type of polarity in development and human disease. PCP is coordinated by long-range Wnt ligand signals, resulting in asymmetric localization of their receptors, the Frizzled (Fz) proteins, and associated signaling cascade. Core Fz/PCP factors are required to interpret polarity within the cell and relay this to neighboring cells. All core Fz/PCP members are evolutionarily conserved and regulate all PCP aspects. This Wnt-pathway is distinct from canonical Wnt-Fz/β-catenin signaling (and correct regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical for development and disease). In Wnt-PCP-signaling Fz's act both, as receptors for Wnts and ligands for its intercellular binding partner(s) Van Gogh/Vang (Vangl1/2 in mammals). The cellular mechanism(s) affecting polarity downstream of either Fz or Vang upon polarized localization remain very poorly understood. The scope and focus of my lab's research and this application is to investigate the mechanistic interactions of long-range PCP signaling and the resulting cell biological read-outs and intracellular responses. Our recent focus has been/is on Vang/Vangl function, as a result of its intercellular interaction with Fz, and the associated cellular response. Our work is and will be also guided by patient derived data and the respective functional dissection of these mutations. Based on exciting ongoing experiments, we will address the physiological significance of Fz-induced Vang phosphorylation and associated kinase function, and how these affect Vang interactions with cytoplasmic effectors. These studies will be aided by including patient data with Vangl1/2 associated neural tube closure defects. In parallel, we are dissecting the intracellular cell biological responses to PCP signaling and how these affect positioning and the mechanistic interplay with cilia associated proteins, with the advantage of being able to do so in non-ciliated Drosophila cells. A combination of in vivo studies and cell culture biochemical experiments will be performed to achieve these goals. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities, ranging from deafness to neural tube closure defects and cancer, or ciliopathies in general. Information acquired will advance our understanding of cellular polarization, and provide medical relevance in many disease contexts.
上皮细胞在两个轴上极化,为其功能,普遍存在的顶-基极性和第二个轴

项目成果

期刊论文数量(0)
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Marek Mlodzik其他文献

Marek Mlodzik的其他文献

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{{ truncateString('Marek Mlodzik', 18)}}的其他基金

Nuclear import of beta-Catenin in Wnt-signaling
Wnt 信号转导中 β-连环蛋白的核输入
  • 批准号:
    9917359
  • 财政年份:
    2020
  • 资助金额:
    $ 60.75万
  • 项目类别:
Nuclear import of beta-Catenin in Wnt-signaling
Wnt 信号转导中 β-连环蛋白的核输入
  • 批准号:
    10094218
  • 财政年份:
    2020
  • 资助金额:
    $ 60.75万
  • 项目类别:
Wnt/Frizzled-PCP signaling in development and disease
发育和疾病中的 Wnt/Frizzled-PCP 信号传导
  • 批准号:
    10631665
  • 财政年份:
    2018
  • 资助金额:
    $ 60.75万
  • 项目类别:
Wnt/Frizzled-PCP signaling in development and disease
发育和疾病中的 Wnt/Frizzled-PCP 信号传导
  • 批准号:
    10397149
  • 财政年份:
    2018
  • 资助金额:
    $ 60.75万
  • 项目类别:
Wnt/Frizzled-PCP signaling in development and disease
发育和疾病中的 Wnt/Frizzled-PCP 信号传导
  • 批准号:
    10159276
  • 财政年份:
    2018
  • 资助金额:
    $ 60.75万
  • 项目类别:
Wnt/Frizzled-PCP signaling in development and disease
发育和疾病中的 Wnt/Frizzled-PCP 信号传导
  • 批准号:
    9486438
  • 财政年份:
    2018
  • 资助金额:
    $ 60.75万
  • 项目类别:
Ubiquitin-like protein modifications in planar cell polarity
平面细胞极性中的泛素样蛋白修饰
  • 批准号:
    8628229
  • 财政年份:
    2014
  • 资助金额:
    $ 60.75万
  • 项目类别:
Ubiquitin-like protein modifications in planar cell polarity
平面细胞极性中的泛素样蛋白修饰
  • 批准号:
    9240642
  • 财政年份:
    2014
  • 资助金额:
    $ 60.75万
  • 项目类别:
A Novel Signaling Pathway in Planar Cell Polarity Establishment
平面细胞极性建立中的新型信号通路
  • 批准号:
    8368456
  • 财政年份:
    2012
  • 资助金额:
    $ 60.75万
  • 项目类别:
A Novel Signaling Pathway in Planar Cell Polarity Establishment
平面细胞极性建立中的新型信号通路
  • 批准号:
    8514671
  • 财政年份:
    2012
  • 资助金额:
    $ 60.75万
  • 项目类别:

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