Developing preclinical xenograft models in zebrafish.

在斑马鱼中开发临床前异种移植模型。

基本信息

  • 批准号:
    10334672
  • 负责人:
  • 金额:
    $ 79.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-01 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Xenograft cell transplantation has transformed our understanding of human disease and has been used extensively to assess regeneration, stem cell self-renewal, and cancer. Yet, mouse xenograft studies are expensive and not easily amenable to imaging engraftment at single cell resolution. By contrast, zebrafish are inexpensive, can be reared in large numbers, and are capable of real-time imaging of fluorescent-labeled cells at single cell resolution. Our group has recently pioneered the use of adult immune-deficient zebrafish for xenograft transplantation of human cancers and blood cells when reared at 37OC. Despite these successes, more needs to be done to develop the next generation of immune compromised zebrafish for long-term xenograft cell transplantation studies. The long-term goal of our work is to develop a universal zebrafish transplantation model to engraft of a wide array of human regenerative and cancer cell types. The overall objective is i) to develop new immune deficient zebrafish models for optimized xenograft engraftment of human cancer, embryonic and induced-pluripotent stem cells (ES and iPSCs), and blood cells and ii) provide much needed tools, methods, and cell biological readouts to directly assess pharmacodynamic responses to radiation, drugs, and cell biological immunotherapies in vivo. The rationale for our research is that zebrafish blood development is highly conserved and that developing zebrafish transplantation models will provide new tools to rapidly assess preclinical therapies in vivo and at single cell resolution. Aim 1 will develop compound mutant and transgenic zebrafish for optimized xenograft cell transplantation. We will develop new models that lack T, B, NK, and macrophage cell function and that transgenically express human cytokines to support the growth of human blood. We will also generate knock-in “genotype-less rag2∆/∆, il2rga−/− zebrafish” to increase throughput in identifying double homozygous mutant animals. Aim 2 will test these models for enhanced engraftment of human cancers, ES, iPSCs, and blood cells. This work is important, because it will provide novel models and experimental protocols to engraft a wide array of regenerative cell types. Aim 3 will dynamically visualize xenograft single cell responses to radiation, combination drug therapies, and immunotherapy in preclinical modeling studies. This work will provide much needed cell biological readouts to directly assess pharmacodynamic responses at single cell resolution across a wide array of therapies. These same imaging tools and approaches can be used in many xenograft models – including patient-derived xenografts (PDXs), ES/IPSCs, and blood. Our work is significant because it will develop the next generation of low-cost, high throughput cell transplantation models that allow direct visualization of engrafted cell behaviors in the context of preclinical therapies. This work will have a positive translational impact by developing preclinical animal models that efficiently engraft a wide array of human tissues. Such broad reaching applications for immune compromised zebrafish spans the mission of many NIH institutes.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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David Michael Langenau其他文献

David Michael Langenau的其他文献

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{{ truncateString('David Michael Langenau', 18)}}的其他基金

Oncogenic Drivers of Rhabdomyosarcoma Cell State, Cancer Stem Cells and Metastasis
横纹肌肉瘤细胞状态、癌症干细胞和转移的致癌驱动因素
  • 批准号:
    10658091
  • 财政年份:
    2023
  • 资助金额:
    $ 79.46万
  • 项目类别:
Mechanisms of aggressive Rhabdomyosarcoma.
侵袭性横纹肌肉瘤的机制。
  • 批准号:
    10560866
  • 财政年份:
    2023
  • 资助金额:
    $ 79.46万
  • 项目类别:
Developing preclinical xenograft models in zebrafish.
在斑马鱼中开发临床前异种移植模型。
  • 批准号:
    10578692
  • 财政年份:
    2022
  • 资助金额:
    $ 79.46万
  • 项目类别:
Stem cell self-renewal programs in rhabdomyosarcoma
横纹肌肉瘤的干细胞自我更新计划
  • 批准号:
    10321242
  • 财政年份:
    2018
  • 资助金额:
    $ 79.46万
  • 项目类别:
New models and therapeutic approaches in alveolar rhabdomyosarcoma
肺泡横纹肌肉瘤的新模型和治疗方法
  • 批准号:
    9899960
  • 财政年份:
    2018
  • 资助金额:
    $ 79.46万
  • 项目类别:
New models and therapeutic approaches in alveolar rhabdomyosarcoma
肺泡横纹肌肉瘤的新模型和治疗方法
  • 批准号:
    10375518
  • 财政年份:
    2018
  • 资助金额:
    $ 79.46万
  • 项目类别:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
T细胞急性淋巴细胞白血病的致癌途径和治疗靶点
  • 批准号:
    10225314
  • 财政年份:
    2017
  • 资助金额:
    $ 79.46万
  • 项目类别:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
T细胞急性淋巴细胞白血病的致癌途径和治疗靶点
  • 批准号:
    9383339
  • 财政年份:
    2017
  • 资助金额:
    $ 79.46万
  • 项目类别:
Oncogenic pathways and therapeutic targets in T cell acute lymphoblastic leukemia
T细胞急性淋巴细胞白血病的致癌途径和治疗靶点
  • 批准号:
    9751256
  • 财政年份:
    2017
  • 资助金额:
    $ 79.46万
  • 项目类别:
Immune Compromised Zebrafish for Cell Transplantation
用于细胞移植的免疫受损斑马鱼
  • 批准号:
    10454455
  • 财政年份:
    2013
  • 资助金额:
    $ 79.46万
  • 项目类别:

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