Paper-based cultures supporting tissue-like structures for biochemical studies of oxygen gradients and screening applications

支持组织样结构的纸基培养物,用于氧梯度的生化研究和筛选应用

基本信息

项目摘要

Project Abstract: Lockett, Matthew Ryen Despite the importance gradients play in regulating tissue formation, structure, and homeostasis there are few analytical tools capable of generating tissue-like environments with experimentally defined oxygen gradi- ents. The tools that are available have not been widely adopted by tissue culture laboratories because they require specialized equipment and engineering expertise to setup, maintain, and analyze. To enable the study of oxygen’s role in directing responses at the cellular, tissue, and organ level new culture platforms are need- ed. My laboratory has been developing a paper-based culture platform for the last four years. This platform is unlike any other. Employing simple technological solutions, we can readily generate 3D cultures with defined extracellular environments, regardless of cell type or tissue structure. The level of experimental control afford- ed by the paper culture platform, makes them a powerful enabling technology to probe cellular responses in well-defined extracellular environments This MIRA application builds upon our prior successes and continues to innovate the paper platform. In par- ticular, we will leverage our ability to generate defined extracellular gradients to study the role of oxygen in regulating cellular phenotype, modulating protein expression and activity, and promoting directed movement. The diffusion-dominated gradients formed in our platform are similar to those that form in healthy tissue, and we are able to generate both healthy tissue environments as well as those resulting from ischemia or poor vascularization. In particular we will: 1) Develop tools to characterize the gradients that form in the paper cul- tures, focusing on oxygen, pH, glucose, and lactate. Through the use of luminescent extracellular, intracellular, and transcription-based sensors we will determine the design rules to generate gradients on demand. Such design rules will help others interested in studying particular aspects of the tissue microenvironment. 2) Evalu- ate differences between immotile and highly invasive cells. These datasets will shed light on the microenvi- ronment’s role—in particular oxygen gradients—in promoting varied cellular responses that result in move- ment, drug resistance, etc. 3) Generate tissue-like co-cultures with physiologically relevant oxygen gradients. By generating liver and breast lumen models, we will be able to experimentally determine how oxygen gradi- ents lead to zonation (liver) and regulate hormone receptor activity (breast). 4) Develop a platform to screen multiple 3D tissue structures in parallel. The ability to generate and evaluate many tissue structures in parallel will greatly improve screening processes to assess liver toxicity and identify potential endocrine disruptors.
项目摘要:洛基特,Matthew Ryen 尽管梯度在调节组织形成、结构和动态平衡方面发挥着重要作用,但 很少有分析工具能够产生具有实验定义的氧气等级的组织状环境- 恩茨。现有的工具尚未被组织培养实验室广泛采用,因为它们 需要专门的设备和工程专业知识来设置、维护和分析。为了使这项研究成为可能 氧在细胞、组织和器官水平上的反应指挥作用需要新的培养平台- 艾德在过去的四年里,我的实验室一直在开发一个纸质文化平台。这个平台是 不同于其他任何人。使用简单的技术解决方案,我们可以轻松地生成具有定义的3D文化 细胞外环境,与细胞类型或组织结构无关。实验对照的水平能够- 由纸文化平台开发,使其成为一项强大的使能技术,以探测细胞响应 定义明确的胞外环境 这款Mira应用程序建立在我们之前的成功基础上,并继续创新纸质平台。在票面上- 我们将利用我们产生定义的细胞外梯度的能力来研究氧气在 调节细胞表型,调节蛋白质表达和活性,促进定向运动。 在我们的平台中形成的以扩散为主的梯度与在健康组织中形成的类似,并且 我们既能产生健康的组织环境,也能产生由缺血或不良引起的组织环境 血管形成。具体来说,我们将:1)开发工具来表征纸张中形成的梯度- 培养,重点是氧气、pH、葡萄糖和乳酸。通过使用发光的细胞外,细胞内, 和基于转录的传感器,我们将确定按需生成梯度的设计规则。是这样的 设计规则将帮助其他对研究组织微环境的特定方面感兴趣的人。2)价值- 吃了静止细胞和高侵袭性细胞之间的差异。这些数据集将揭示微环境-- 环境的作用-特别是氧气梯度-在促进不同的细胞反应导致移动- 3)产生具有生理上相关的氧气梯度的组织状共培养。 通过建立肝脏和乳房腔模型,我们将能够在实验上确定氧气浓度如何变化。 ENTs导致分区(肝脏)和调节激素受体活动(乳房)。4)开发筛选平台 并行的多个3D组织结构。并行生成和评估多个组织结构的能力 将极大地改进筛查过程,以评估肝脏毒性并确定潜在的内分泌干扰物。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
HepaRG cells adopt zonal-like drug-metabolizing phenotypes under physiologically relevant oxygen tensions and Wnt/β-catenin signaling.
HepaRG 细胞在生理相关的氧张力和 Wnt/β-连环蛋白信号传导下采用带状药物代谢表型。
Spatially resolved quantification of drug metabolism and efficacy in 3D paper-based tumor mimics.
  • DOI:
    10.1016/j.aca.2021.339091
  • 发表时间:
    2021-11-22
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Larson TS;Glish GL;Lockett MR
  • 通讯作者:
    Lockett MR
Paper-Based Coculture Platform to Evaluate the Effects of Fibroblasts on Estrogen Signaling in ER+ Breast Cancers.
  • DOI:
    10.1021/acsmeasuresciau.3c00032
  • 发表时间:
    2023-12-20
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sitte, Zachary R;Miranda Buzetta, Abel Andre;Jones, Sarina J;Lin, Zhi-Wei;Whitman, Nathan Ashbrook;Lockett, Matthew R
  • 通讯作者:
    Lockett, Matthew R
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Matthew Ryen Lockett其他文献

Matthew Ryen Lockett的其他文献

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{{ truncateString('Matthew Ryen Lockett', 18)}}的其他基金

Developing an in vitro to in vivo pipeline of mammary gland exposure-response relationships to per- and poly-fluoroalkyl substances (PFAS)
开发乳腺对全氟烷基物质和多氟烷基物质 (PFAS) 的暴露-反应关系的体外到体内管道
  • 批准号:
    10654671
  • 财政年份:
    2020
  • 资助金额:
    $ 36.54万
  • 项目类别:
Developing an in vitro to in vivo pipeline of mammary gland exposure-response relationships to per- and poly-fluoroalkyl substances (PFAS)
开发乳腺对全氟烷基物质和多氟烷基物质 (PFAS) 的暴露-反应关系的体外到体内管道
  • 批准号:
    10271405
  • 财政年份:
    2020
  • 资助金额:
    $ 36.54万
  • 项目类别:
Developing an in vitro to in vivo pipeline of mammary gland exposure-response relationships to per- and poly-fluoroalkyl substances (PFAS)
开发乳腺对全氟烷基物质和多氟烷基物质 (PFAS) 的暴露-反应关系的体外到体内管道
  • 批准号:
    10440478
  • 财政年份:
    2020
  • 资助金额:
    $ 36.54万
  • 项目类别:
Paper-based cultures supporting tissue-like structures for biochemical studies of oxygen gradients and screening applications
支持组织样结构的纸基培养物,用于氧梯度的生化研究和筛选应用
  • 批准号:
    10192747
  • 财政年份:
    2018
  • 资助金额:
    $ 36.54万
  • 项目类别:

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