Four-dimensional prediction and quantification of how physical forces impact organogenesis in zebrafish

物理力如何影响斑马鱼器官发生的四维预测和量化

基本信息

  • 批准号:
    10271304
  • 负责人:
  • 金额:
    $ 45.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-25 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Defects in programmed cell shape changes during embryonic development can disrupt organ morphogenesis and cause structural birth defects. There are fundamental gaps in our understanding of how cells change their shape during organ formation. While the biochemical signals and morphogen gradients that help govern organogenesis are well-studied, evidence is growing that robust control of organ form and function often also depends on multiple mechanical mechanisms that remain poorly understood. Thus, there is a critical need to tease apart how multiple mechanisms – including tissue-scale dynamic forces and cell-autonomous contractile forces – work together to generate “mechanical gradients” that program cell and organ shape during organ formation. A challenge is that mechanical perturbations that affect the entire embryo often result in the same global phenotype, making it difficult to pinpoint the role of each mechanism. Our long- term goal is to develop a combined cell biology and modeling toolkit that allows us to predict cell-scale phenotypes and appropriate perturbations that can be used to distinguish between multiple mechanical mechanisms. This project uses Kupffer’s vesicle (KV), a transient epithelial organ that establishes left-right asymmetry in the zebrafish embryo, as a model system. No upstream biochemical signaling gradients have been identified that regulate KV cell shapes as required for left-right patterning, but multiple mechanical mechanisms have been implicated. Preliminary results – from (4D = 3D + time) experimental perturbations and measurements of single KV cell shapes, and novel mathematical models that simulate interacting 3D tissue structures while retaining cell-scale resolution – lead us to formulate our central hypothesis that cell shape changes critical for KV organogenesis result from mechanical gradients generated by interactions between the KV and surrounding tissue structures as well as cell-autonomous contractile forces from inside KV. The goal of Aim 1 is to determine how interactions between KV and notochord impact cell shape changes. 4D modeling predictions for cell shapes and cell movement combined with live in vivo imaging and localized laser ablations will determine how asymmetric forces generated by the rod-like notochord impact KV cell shape changes during organogenesis. The goal of Aim 2 is to understand mechanisms by which actomyosin contractility in surrounding tailbud cells and inside KV generate KV cell shape changes. Novel mathematical models will predict how localized optical perturbations to tailbud mechanics, as well as perturbations to volume and cell- autonomous contractility in cells inside the KV, affect KV organ shape. Key outputs include a modeling toolkit for high-throughput simulations of dynamic interactions between complex 3D tissue structures complemented by a cell biology toolkit that tests model predictions with spatially and temporally modulated activation of biomechanical and biochemical signaling molecules. These results will pinpoint mechanical mechanisms that regulate organogenesis, and may ultimately aid in the prediction or prevention of birth defects.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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JEFFREY D AMACK其他文献

JEFFREY D AMACK的其他文献

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{{ truncateString('JEFFREY D AMACK', 18)}}的其他基金

Four-dimensional prediction and quantification of how physical forces impact organogenesis in zebrafish
物理力如何影响斑马鱼器官发生的四维预测和量化
  • 批准号:
    10121167
  • 财政年份:
    2020
  • 资助金额:
    $ 45.35万
  • 项目类别:
Four-dimensional prediction and quantification of how physical forces impact organogenesis in zebrafish
物理力如何影响斑马鱼器官发生的四维预测和量化
  • 批准号:
    10472046
  • 财政年份:
    2020
  • 资助金额:
    $ 45.35万
  • 项目类别:
Regulation of Ciliated Cells that Control Cardiac Laterality
控制心脏偏侧性的纤毛细胞的调节
  • 批准号:
    7851355
  • 财政年份:
    2009
  • 资助金额:
    $ 45.35万
  • 项目类别:
Regulation of Ciliated Cells that Control Cardiac Laterality
控制心脏偏侧性的纤毛细胞的调节
  • 批准号:
    7634059
  • 财政年份:
    2009
  • 资助金额:
    $ 45.35万
  • 项目类别:
Regulation of Ciliated Cells that Control Cardiac Laterality
控制心脏偏侧性的纤毛细胞的调节
  • 批准号:
    8429442
  • 财政年份:
    2009
  • 资助金额:
    $ 45.35万
  • 项目类别:
Regulation of Ciliated Cells that Control Cardiac Laterality
控制心脏偏侧性的纤毛细胞的调节
  • 批准号:
    8150627
  • 财政年份:
    2009
  • 资助金额:
    $ 45.35万
  • 项目类别:
Role of Dorsal Forerunner Cells in Left/Right Patterning
背侧先行细胞在左/右图案形成中的作用
  • 批准号:
    6992672
  • 财政年份:
    2004
  • 资助金额:
    $ 45.35万
  • 项目类别:
Role of Dorsal Forerunner Cells in Left/Right Patterning
背侧先行细胞在左/右图案形成中的作用
  • 批准号:
    6850700
  • 财政年份:
    2004
  • 资助金额:
    $ 45.35万
  • 项目类别:
Role of Dorsal Forerunner Cells in Left/Right Patterning
背侧先行细胞在左/右图案形成中的作用
  • 批准号:
    6738235
  • 财政年份:
    2004
  • 资助金额:
    $ 45.35万
  • 项目类别:

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