Fibronectin Mechanics and Signaling in Epithelial to Mesenchymal Transition

上皮间质转化中的纤连蛋白力学和信号传导

基本信息

  • 批准号:
    9318153
  • 负责人:
  • 金额:
    $ 4.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Epithelial to Mesenchymal Transition (EMT) is a process by which a distinct change in the phenotype and function of epithelial cells causes them to convert into mesenchymal cells. EMT is involved in facilitating the progression of breast cancer to an invasive disease. Therefore, there is a strong need to fully understand the mechanism for the induction of EMT. Recent advances point to the fact that EMT is controlled by a combination of growth factors (gfs) and substrate stiffness. Transforming Growth Factor- (TGF-), a gf known to induce EMT in breast cancer formation, induces EMT on rigid surfaces and apoptosis on compliant surfaces. It is our belief that a combination of mechanical signals, gf signals, and the type of extracellular matrix (ECM) proteins assembled by cells together drive the process of EMT. This research will focus on the ECM protein fibronectin (FN), which assembles into elastic, insoluble fibrils. FN’s ability to serves as a gf delivery system along with its assembly by cell-generated forces, which become larger on stiffer surfaces, led us to examine the following hypothesis: increased tissue stiffness drives FN assembly, which exposes cryptic binding sites for various gfs, such as TGF-β1, and creates a high concentration of these gfs at the cell surface, which in turn drives EMT. In this project we will investigate three aims: (1) evaluate the effect of inhibiting FN fibrillogenesis and GF localization on TGF-β1-induced EMT, (2) probe the role of gf tethering to the FN matrix in spatial patterning of EMT, and (3) assess the effect of varying substrate rigidity in the absence of FN assembly on the generation of cellular traction forces in epithelial monolayers. FN assembly will be inhibited with a protein fragment of the bacterial cell wall protein adhesion F1, which has previously been shown to inhibit FN fibril assembly without altering FN expression. The correlation between FN fibril assembly and EMT marker presence will be observed qualitatively through immunofluorescence. Protein expression will be quantified via Western blotting, and mRNA expression will be determined with RT-PCR. FN fibril area and gf co-localization will be quantified with a self- written image processing algorithm. Microcontact-printed patterns will be generated from ECM protein coated polydimethylsiloxane stamps. Varying substrate rigidities will be obtained by preparing polyacrylamide gels with elastic moduli ranging from 0.4 kPa to 60 kPa, and microfabricated pillar arrays will be produced with 2 micron diameters and heights varying from 5 to 15 microns. These substrate stiffnesses represent the range from native breast tissue to fibrotic tissue. The knowledge gained from this study will elucidate how physical changes within the breast tumor microenvironment regulate cancer biology. By establishing a connection between FN assembly and the misregulation of EMT in cancer progression, we hope to potentially identify novel targets for cancer therapy.
项目总结

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Spatial Gradients of E-Cadherin and Fibronectin in TGF-β1-Treated Epithelial Colonies Are Independent of Fibronectin Fibril Assembly.
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Lauren A. Griggs其他文献

The YsrS Paralog DygS Has the Capacity To Activate Expression of the Yersinia enterocolitica Ysa Type III Secretion System
YsrS Paralog DygS 具有激活小肠结肠炎耶尔森氏菌 Ysa III 型分泌系统表达的能力
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    K. Walker;Lauren A. Griggs;Markus W. Obrist;Addys Bode;R. Patrick Summers;Virginia L. Miller
  • 通讯作者:
    Virginia L. Miller

Lauren A. Griggs的其他文献

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{{ truncateString('Lauren A. Griggs', 18)}}的其他基金

Fibronectin Mechanics and Signaling in Epithelial to Mesenchymal Transition
上皮间质转化中的纤连蛋白力学和信号传导
  • 批准号:
    9195389
  • 财政年份:
    2016
  • 资助金额:
    $ 4.36万
  • 项目类别:

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