Cell membrane-targeting proteoglycan chimeras as selective growth factor signaling actuators

作为选择性生长因子信号传导执行器的细胞膜靶向蛋白聚糖嵌合体

基本信息

  • 批准号:
    10588085
  • 负责人:
  • 金额:
    $ 49.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary Growth factor (GF)-based therapies hold great promise for tissue engineering, cancer treatment, and regenera- tive medicine but controlling their activity and selectivity can be challenging. GFs act as ligands for membrane- receptors controlling signaling cascades that drive gene expression and cellular functions, such as proliferation and differentiation. Tools that can selectively activate or suppress GF-mediated signaling activity in cells are needed to achieve control over the activity of these molecules and improve their therapeutic properties. Heparan sulfate (HS) proteoglycans (PGs), while often overlooked, are uniquely suited for this purpose, as they often serve as coreceptors for GFs at the cell surface. By promoting the formation of complexes between GFs and their receptors, they balance competing signaling pathways and regulate cellular responses. While the structure and activity of HS on cells can be controlled, to some extent, through genetic engineering of their biosynthesis, chemical tools for remodeling cell-sulfate HS to attain GF-binding specificity would be much mor general and better suited for therapeutic applications. This project establishes such tools, termed neoPG chimeras, that will be able to selectively activate or inhibit GF signaling activity in cells. This will be achieved by taking advantage of the GF-binding selectivities of recombinant HS polysaccharides produced through systematic mutation of HS biosynthetic enzymes in laboratory cell lines. The recombinant HS polysaccharides will be harvested, character- ized for GF binding specificity and merged with functional elements for targeting to the cells. Membrane targeting neoPG chimeras will be developed to promote GF association with receptors at the cell surface and promote GF signaling activity (Aim 1). Lysosome-targeting neoPG chimeras will be used to drive extracellular GFs into the cells for degradation, thus inhibiting signaling activity (Aim 2). The focus of this study will be on establishing and validating neoPG chimeras as actuators of signaling by members of the Fibroblast Growth Factor family of pro- teins in the context of cellular proliferation and differentiation. However, many other classes of GFs require cell surface HS for function and the new tools are expected to find broad application in many different aspects of biomedical research and GF-based therapies.
项目总结

项目成果

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Kamil Godula其他文献

Kamil Godula的其他文献

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{{ truncateString('Kamil Godula', 18)}}的其他基金

Glycan engineering via exoplasmic Golgi shuttle of glycosylation building blocks and modulators
通过糖基化构件和调节剂的外质高尔基体穿梭进行聚糖工程
  • 批准号:
    9809104
  • 财政年份:
    2019
  • 资助金额:
    $ 49.71万
  • 项目类别:
In vivo glycan engineering at the cell-matrix interface to control stem cell fate
细胞-基质界面的体内聚糖工程控制干细胞命运
  • 批准号:
    8955575
  • 财政年份:
    2015
  • 资助金额:
    $ 49.71万
  • 项目类别:
NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging
新蛋白聚糖作为再生医学和生物成像的合成材料
  • 批准号:
    8719535
  • 财政年份:
    2013
  • 资助金额:
    $ 49.71万
  • 项目类别:
NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging
新蛋白聚糖作为再生医学和生物成像的合成材料
  • 批准号:
    8728007
  • 财政年份:
    2013
  • 资助金额:
    $ 49.71万
  • 项目类别:
NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging
新蛋白聚糖作为再生医学和生物成像的合成材料
  • 批准号:
    8916112
  • 财政年份:
    2013
  • 资助金额:
    $ 49.71万
  • 项目类别:
NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging
新蛋白聚糖作为再生医学和生物成像的合成材料
  • 批准号:
    8091489
  • 财政年份:
    2011
  • 资助金额:
    $ 49.71万
  • 项目类别:
NeoProteoglycans as synthetic materials for regenerative medicine and bioimaging
新蛋白聚糖作为再生医学和生物成像的合成材料
  • 批准号:
    8286932
  • 财政年份:
    2011
  • 资助金额:
    $ 49.71万
  • 项目类别:

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以额叶功能为中心的汽车驾驶能力评价方法的建立及其在事故预测中的应用
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