Identifying pathways required for integration of kidney organoid and host epithelia

确定肾类器官和宿主上皮细胞整合所需的途径

基本信息

  • 批准号:
    10053465
  • 负责人:
  • 金额:
    $ 62.78万
  • 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:
    2020-09-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary Kidney disease is the 9th leading cause of death in the U.S. Because few therapies exist to prevent or slow progression, over 700,000 patients have End Stage Renal Disease. These patients are treated with dialysis or renal transplant, the latter resulting in markedly superior survival. However, kidney donors are limited and there is an important unmet need for strategies that enhance renal repair or generate new nephrons for renal replacement. Pluripotent stem cell derived organoids display key features of differentiated kidney tubules and glomerular structures in vitro, and we have shown that they generate patterned nephrons in vivo displaying kidney functions such as filtration and glucose uptake by the proximal tubule. To develop this technology for renal replacement, stem cell derived tubules must be connected to host tubules for urinary output. Our recent work in the zebrafish demonstrated that FGF signaling acts as a chemotactic signal to recruit and polarize cells at sites of new nephron formation and canonical Wnt signaling is required for invasive cell rearrangement to connect tubule lumens. Additional signaling pathways including non-canonical wnt signaling are also likely to play a role in tubule interconnection. To fully explore the requirements for tubule interconnection we have established a synergistic, three-part discovery platform comprising 1) genetic analysis of in vivo new nephron addition in the regenerating zebrafish adult kidney, 2) in vitro 3D cell culture analysis of mammalian epithelial fusion, and 3) in vivo stem cell-derived kidney organoid engraftment to a host mouse collecting system. We will combine these approaches to analyze multiple steps of the tubule fusion process involving 1) recruitment of nephron progenitor cells to target epithelia, 2) removal of intervening ECM/basement membranes, 3) patterned collective cell invasion of target epithelia, and 4) establishment of a continuous patent new lumen to convey the nephron filtrate. These studies will provide important new insights about an essential but understudied cellular mechanism that will be required for in vivo engraftment of new kidney tissue-based renal regeneration therapies.
项目总结

项目成果

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IAIN A. DRUMMOND其他文献

IAIN A. DRUMMOND的其他文献

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{{ truncateString('IAIN A. DRUMMOND', 18)}}的其他基金

Mechanisms of tubule interconnection
肾小管互连机制
  • 批准号:
    10199303
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
Identifying pathways required for integration of kidney organoid and host epithelia
确定肾类器官和宿主上皮细胞整合所需的途径
  • 批准号:
    10248562
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
MDIBL Symposium on Stem Cells and Aging
MDIBL干细胞与衰老研讨会
  • 批准号:
    10237394
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
Identifying pathways required for integration of kidney organoid and host epithelia
确定肾类器官和宿主上皮细胞整合所需的途径
  • 批准号:
    10428383
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
MDIBL Symposium on Stem Cells and Aging
MDIBL干细胞与衰老研讨会
  • 批准号:
    10459346
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
Identifying pathways required for integration of kidney organoid and host epithelia
确定肾类器官和宿主上皮细胞整合所需的途径
  • 批准号:
    10645060
  • 财政年份:
    2020
  • 资助金额:
    $ 62.78万
  • 项目类别:
Mechanisms of tubule interconnection
肾小管互连机制
  • 批准号:
    9547613
  • 财政年份:
    2015
  • 资助金额:
    $ 62.78万
  • 项目类别:
Mechanisms of tubule interconnection
肾小管互连机制
  • 批准号:
    8995457
  • 财政年份:
    2015
  • 资助金额:
    $ 62.78万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10437779
  • 财政年份:
    2013
  • 资助金额:
    $ 62.78万
  • 项目类别:
Comparative Biology of Tissue Repair, Regeneration and Aging
组织修复、再生和衰老的比较生物学
  • 批准号:
    10437777
  • 财政年份:
    2013
  • 资助金额:
    $ 62.78万
  • 项目类别:

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