Molecular dissection of Hematopoietic Stem Cell specification triggered by inflammatory mediators

炎症介质触发造血干细胞规范的分子解剖

基本信息

  • 批准号:
    10346708
  • 负责人:
  • 金额:
    $ 39.34万
  • 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:
    2022-02-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Due to the unique property of hematopoietic stem cells (HSCs) to reconstitute the entire blood system of the organism, these stem cells are utilized clinically to treat blood disorders. The possibility of culturing and expanding HSCs in vitro would make hematopoietic stem cell transplantation (HSCT)-based therapies more feasible. However, this has eluded the field for more than three decades, necessitating a closer examination of the native developmental mechanisms that govern the emergence of HSCs. Many years of investigation have revealed that HSCs require multiple molecular inputs for proper specification, including activity of the Notch, nitric oxide (NO), Wnt, FGF, and BMP signaling pathways. In addition, inflammatory signaling (Tnfa, NF-kB, Tlr4, interferons, Il1b and inflammasome) have been recently reported as a novel group of HSC fate modulators, yet the underlying molecular mechanisms are unclear. Addressing this knowledge gap will be critical to help develop in vitro protocols for the generation of patient-specific HSCs. The goal of this proposal is to reveal in vivo the inflammatory network that unlocks HSC specification from the hemogenic endothelium (HE), and its relationship with the Notch and nitric oxide pathways. To attain this goal, the following three specific aims will be pursued: (1) Identify the role of Nod1 signaling during HSC development; (2) determine the mechanism of NF-kB-directed HSC specification; and (3) analyze the impact of the NOD1/RIPK2/NF-kB inflammatory axis on human pluripotent stem cell-derived definitive hematopoietic progenitor cells. Since hematopoietic development is highly conserved between vertebrate species, the zebrafish model provides a unique opportunity to circumvent the challenges of in utero experimentation, permitting non-invasive experiments that avoid the artifactual inflammation caused by cellular stress. To achieve this application's goals, a combination of novel zebrafish reporter and mutant lines, new methods to perform epigenomic and transcriptomic profiling of the HE by CUT&RUN-sequencing and RNA-sequencing, live imaging of HSC development by confocal and light-sheet microscopy, qPCR, FACS-sorting, and lineage tracing using Cre- mediated reporter systems will be utilized. In addition, to translate these in vivo findings to human health, this proposal will be complemented with a model of hematopoietic differentiation from human pluripotent stem cells (hPSCs). Upon successful completion of the proposed research, a previously undescribed inflammatory pathway affecting HSC specification will be identified, in addition to the central molecular mechanism by which inflammatory signaling drives HSC fate and crosstalk to other main HSC inductors. These new findings could provide key insights needed to instruct HSC fate, informing in vitro approaches to generate HSCs from pluripotent precursors for the treatment of blood disorders.
项目总结

项目成果

期刊论文数量(0)
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Raquel Espín Palazón其他文献

Raquel Espín Palazón的其他文献

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{{ truncateString('Raquel Espín Palazón', 18)}}的其他基金

Molecular dissection of Hematopoietic Stem Cell specification triggered by inflammatory mediators
炎症介质触发造血干细胞规范的分子解剖
  • 批准号:
    10552605
  • 财政年份:
    2022
  • 资助金额:
    $ 39.34万
  • 项目类别:
In vivo assessment of granulin dependent myeloid cell formation
颗粒蛋白依赖性骨髓细胞形成的体内评估
  • 批准号:
    10201594
  • 财政年份:
    2020
  • 资助金额:
    $ 39.34万
  • 项目类别:
In vivo assessment of granulin dependent myeloid cell formation
颗粒蛋白依赖性骨髓细胞形成的体内评估
  • 批准号:
    10043081
  • 财政年份:
    2020
  • 资助金额:
    $ 39.34万
  • 项目类别:
The impact of inflammation on hematopoietic stem cell specification
炎症对造血干细胞规范的影响
  • 批准号:
    10475908
  • 财政年份:
    2017
  • 资助金额:
    $ 39.34万
  • 项目类别:
The impact of inflammation on hematopoietic stem cell specification
炎症对造血干细胞规范的影响
  • 批准号:
    10016274
  • 财政年份:
    2017
  • 资助金额:
    $ 39.34万
  • 项目类别:
The impact of inflammation on hematopoietic stem cell specification
炎症对造血干细胞规范的影响
  • 批准号:
    10242117
  • 财政年份:
    2017
  • 资助金额:
    $ 39.34万
  • 项目类别:
The impact of inflammation on hematopoietic stem cell specification
炎症对造血干细胞规范的影响
  • 批准号:
    9432324
  • 财政年份:
    2017
  • 资助金额:
    $ 39.34万
  • 项目类别:

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