Application of progenitor niche signals to ex vivo nephrogenesis

祖细胞生态位信号在离体肾发生中的应用

基本信息

  • 批准号:
    9297088
  • 负责人:
  • 金额:
    $ 135.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-15 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Approximately 500,000 Americans have end stage renal disease, in which kidney function is insufficient to sustain life. Organ function can be supplemented by dialysis in these individuals; however the 10 year survival rate for individuals on dialysis is just over 10%. Survival rates are much better for patients receiving a kidney transplant but organ supply does not match demand. Ex vivo organogenesis has the potential both to provide functional tissue for renal replacement therapy and to provide research tools with which we can understand the causes of chronic kidney disease and identify new therapies. Furthermore, defining signals that functionally direct nephrogenesis may identify pathways that can be manipulated to augment the regenerative response of the injured kidney in vivo. Our group is able to promote nephrogenesis in cultures of purified primary nephron progenitor cells derived from human stem cells and mouse embryonic kidneys. However, we have identified two key obstacles that must be overcome if this discovery is to have significant impact on human health. First, we must recreate signaling environments that promote progenitor cell proliferation and differentiation in order to obtain sufficient tubule mass for functional analysis. Second, we must devise ex vivo tissue architecture that supports differentiation of arrayed nephrons with vascular connections that are appropriately patterned. The long-term goal of this proposal is to define the tissue architecture and cell signaling microenvironments required to promote the generation of appropriately patterned nephrons in culture. We will investigate signaling mechanisms that are sufficient to promote NPC renewal and differentiation and apply these findings to the development of ex vivo nephron devices using silk protein as a scaffolding biomaterial. Our data show that NPCs efficiently colonize silk and that nephron tubules form in this material. Silk is the material of choice because it is already in clinical use and it is scalale, allowing us to generate structures dimensioned for mouse or human. We will leverage the strengths of the project investigators in kidney and endothelial development as well as bioengineering to develop an integrated, multi-cellular, patterned, functional nephron in vitro. State of the art, innovative technologies will be applied to NPCs differentiated from both human embryonic stem cells and embryonic mouse kidneys. Novel scaffolding and matrix formulations that allow organized 3D organogenesis of tissues in culture will be explored. The investigative group has a 10-year history of collaboration, which is particularly evident in the integrated natur of our preliminary data. We will leverage this program to develop a seamless exchange of engineering and signaling expertise, materials and intellectual innovation between all four laboratories. The program therefore includes a framework for continual scientific exchange including a data tracking website, a bi-monthly schedule of group meetings and face-to-face meetings approximately every 6 months.
 描述(由申请人提供):大约50万美国人患有终末期肾病,其中肾功能不足以维持生命。在这些个体中,器官功能可以通过透析得到补充;然而,透析个体的10年生存率仅略高于10%。接受肾移植的患者的存活率要好得多,但器官供应与需求不匹配。离体器官发生既有可能为肾脏替代治疗提供功能组织,也有可能为我们提供研究工具,使我们能够了解慢性肾脏疾病的原因并确定新的治疗方法。此外,定义在功能上指导肾发生的信号可以识别可以被操纵以增强体内受损肾脏的再生反应的途径。我们的研究小组能够促进来自人干细胞和小鼠胚胎肾的纯化的原代肾单位祖细胞的培养。然而,我们已经确定了两个关键障碍,如果这一发现要对人类健康产生重大影响,就必须克服。首先,我们必须重建促进祖细胞增殖和分化的信号环境,以获得足够的小管质量进行功能分析。第二,我们必须设计离体组织结构,以支持具有适当模式的血管连接的阵列肾单位的分化。这项提案的长期目标是确定组织结构和细胞信号微环境,以促进在培养中产生适当的模式化肾单位。我们将研究足以促进NPC更新和分化的信号传导机制,并将这些发现应用于使用丝蛋白作为支架生物材料的离体肾单位装置的开发。我们的数据表明,NPC有效地殖民丝和肾单位小管形成在这种材料。丝是首选的材料,因为它已经在临床上使用,它是scalale,使我们能够生成小鼠或人类尺寸的结构。我们将利用项目研究人员在肾脏和内皮发育以及生物工程方面的优势,在体外开发一个集成的、多细胞的、有模式的、功能性肾单位。最先进的创新技术将应用于从人类胚胎干细胞和胚胎小鼠肾脏分化的NPC。将探索新的支架和基质制剂,使组织在文化中有组织的3D器官发生。该调查小组有10年的合作历史,这在我们初步数据的综合性质中尤为明显。我们将利用这一计划,在所有四个实验室之间发展工程和信号专业知识,材料和智力创新的无缝交流。因此,该计划包括一个持续科学交流的框架,包括一个数据跟踪网站,两个月一次的小组会议和大约每6个月一次的面对面会议。

项目成果

期刊论文数量(0)
专著数量(0)
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专利数量(0)

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Thomas Joseph Carroll其他文献

NuMI Beam Monitoring Simulation and Data Analysis
NuMI 光束监测仿真和数据分析
  • DOI:
    10.3390/psf2023008073
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yiding Yu;Thomas Joseph Carroll;Sudeshna Ganguly;Karol Lang;Eduardo Ossorio;P. Snopok;Jennifer Thomas;D. A. Wickremasinghe;K. Yonehara
  • 通讯作者:
    K. Yonehara

Thomas Joseph Carroll的其他文献

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{{ truncateString('Thomas Joseph Carroll', 18)}}的其他基金

Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
  • 批准号:
    10670749
  • 财政年份:
    2021
  • 资助金额:
    $ 135.67万
  • 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
  • 批准号:
    10316848
  • 财政年份:
    2021
  • 资助金额:
    $ 135.67万
  • 项目类别:
Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
  • 批准号:
    10295980
  • 财政年份:
    2021
  • 资助金额:
    $ 135.67万
  • 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
  • 批准号:
    10445327
  • 财政年份:
    2021
  • 资助金额:
    $ 135.67万
  • 项目类别:
The Role of Renal Interstitium in Kidney Development
肾间质在肾脏发育中的作用
  • 批准号:
    10621859
  • 财政年份:
    2021
  • 资助金额:
    $ 135.67万
  • 项目类别:
Application of Progenitor Niche Signals to Ex Vivo Nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
  • 批准号:
    10260117
  • 财政年份:
    2020
  • 资助金额:
    $ 135.67万
  • 项目类别:
Mechanisms of Disease
疾病机制
  • 批准号:
    10654560
  • 财政年份:
    2019
  • 资助金额:
    $ 135.67万
  • 项目类别:
Mechanisms of Disease
疾病机制
  • 批准号:
    10440328
  • 财政年份:
    2019
  • 资助金额:
    $ 135.67万
  • 项目类别:
Application of progenitor niche signals to ex vivo nephrogenesis
祖细胞生态位信号在离体肾发生中的应用
  • 批准号:
    9981392
  • 财政年份:
    2019
  • 资助金额:
    $ 135.67万
  • 项目类别:
Engineering erythropoietin-producing cells
工程化促红细胞生成素生成细胞
  • 批准号:
    9516535
  • 财政年份:
    2015
  • 资助金额:
    $ 135.67万
  • 项目类别:

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