Physiologic Regulation of Hematopoiesis by Notch

Notch对造血的生理调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Despite the increasingly recognized role of inflammation in cancer maintenance and progression, the contribution of specific "inflammatory" bone marrow (BM) niches to the regulation of normal and malignant hematopoiesis is largely unexplored. Evidence supporting a non-cell-autonomous role for Notch signaling in the regulation of hematopoiesis has recently emerged; however, the cellular and molecular mechanism(s) by which Notch regulates the integrity of the BM niche are still poorly understood. By using a Notch/RBPJ loss-of- function model, we showed that loss of RBPJ results in an inflammatory state of the BM microenvironment, leading to aberrant expansion of myeloid progenitors. We demonstrated that RBPJ functions as a transcriptional repressor of the microRNA miR-155, a microRNA involved in inflammation and tumorigenesis. We observed that persistent miR-155 up-regulation due to loss of RBPJ transcriptional repression induces NF-kB activation and a global state of inflammation in the BM niche, particularly in endothelial cells, leading to an uncontrolled expansion of myeloid cells and eventually to the development of a myeloproliferative disease. Of note, analysis of patients affected by myeloproliferative neoplasia (MPN) revealed elevated expression of miR155 in the BM. Based on these results, we hypothesize that Notch signaling contributes to hematopoietic homeostasis by regulating the level of the inflammatory tonus in the BM vascular niche. Thus, while transitory inhibition of Notch signaling in the BM microenvironment may trigger a physiologic inflammatory circuitry in response to BM injury, continuous inhibition of Notch signaling may contribute to the development or progression of myeloproliferative disorders. Focusing on the regulation of hematopoiesis by the BM niche and using several animal models, we propose: 1) to define the role of endothelial Notch signaling in regulating the integrity of the BM niche; 2) to determine how miR155 regulates NF-Kb activation and to map the Notch/miR155/NF-kB circuitry and its impact on myelopoiesis, and 3) to dissect the molecular underpins of the Notch/miR155/NF-kB pathway in human MPN. We believe that these studies will provide critical insights into the molecular mechanisms regulating the interactions of hematopoietic cells with their supportive niches in the BM during conditions of stress and malignancy, and that will lead to strategies to target inflammation and disease progression in MPN.
描述(申请人提供):尽管炎症在癌症维持和发展中的作用日益得到认可,但特定的“炎性”骨髓(BM)壁龛对正常和恶性造血调节的贡献在很大程度上还没有被探索。最近出现了支持Notch信号在造血调控中的非细胞自主作用的证据;然而,Notch调节骨髓生态位完整性的细胞和分子机制(S)仍然知之甚少。通过使用Notch/RBPJ功能丧失模型,我们发现RBPJ的丧失导致骨髓微环境的炎症状态,导致髓系祖细胞的异常扩张。我们证明了RBPJ作为microRNA miR-155的转录抑制因子,miR-155是一种参与炎症和肿瘤发生的microRNA。我们观察到,由于RBPJ转录抑制缺失而导致的miR-155持续上调诱导了核因子-kB的激活和骨髓利基细胞,特别是内皮细胞的全局性炎症状态,导致髓系细胞的失控扩张,最终导致骨髓增殖性疾病的发展。值得注意的是,对受骨髓增生性肿瘤(MPN)影响的患者的分析显示,miR155在骨髓中的表达升高。基于这些结果,我们假设Notch信号通过调节BM血管壁龛中炎症张力的水平来促进造血稳态。因此,尽管骨髓微环境中Notch信号的短暂抑制可能触发反应骨髓损伤的生理性炎症回路,但持续抑制Notch信号可能有助于骨髓增生性疾病的发展或进展。着眼于骨髓生态位对造血的调控,并使用几种动物模型,我们建议:1)确定内皮细胞Notch信号在调节BM生态位完整性中的作用;2)确定miR155如何调节NF-KB的激活,并绘制Notch/miR155/NF-kB电路及其对骨髓生成的影响图;3)剖析人MPN中Notch/miR155/NF-kB通路的分子基础。我们相信,这些研究将为在应激和恶性条件下调节骨髓中造血细胞与其支持微环境相互作用的分子机制提供关键的见解,并将导致针对MPN的炎症和疾病进展的策略。

项目成果

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Nadia Carlesso其他文献

Nadia Carlesso的其他文献

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{{ truncateString('Nadia Carlesso', 18)}}的其他基金

Targeting the Microenvironment/Oncogene Cooperation to treat poor prognosis T-ALL
靶向微环境/癌基因合作治疗预后不良的 T-ALL
  • 批准号:
    10659661
  • 财政年份:
    2023
  • 资助金额:
    $ 39.71万
  • 项目类别:
Bone Marrow Niche dysfunction in sickle cell disease
镰状细胞病的骨髓生态位功能障碍
  • 批准号:
    10250697
  • 财政年份:
    2021
  • 资助金额:
    $ 39.71万
  • 项目类别:
Bone Marrow Niche dysfunction in sickle cell disease
镰状细胞病的骨髓生态位功能障碍
  • 批准号:
    9927706
  • 财政年份:
    2019
  • 资助金额:
    $ 39.71万
  • 项目类别:
Inflammation as determinant of clonal selection in MPN progression
炎症是 MPN 进展中克隆选择的决定因素
  • 批准号:
    9788508
  • 财政年份:
    2018
  • 资助金额:
    $ 39.71万
  • 项目类别:
Inflammation as determinant of clonal selection in MPN progression
炎症是 MPN 进展中克隆选择的决定因素
  • 批准号:
    10191009
  • 财政年份:
    2018
  • 资助金额:
    $ 39.71万
  • 项目类别:
Physiologic Regulation of Hematopoiesis by Notch
Notch对造血的生理调节
  • 批准号:
    8927618
  • 财政年份:
    2014
  • 资助金额:
    $ 39.71万
  • 项目类别:
Physiologic Regulation of Hematopoiesis by Notch
Notch对造血的生理调节
  • 批准号:
    9136855
  • 财政年份:
    2014
  • 资助金额:
    $ 39.71万
  • 项目类别:
Physiologic Regulation of Hematopoiesis by Notch
Notch对造血的生理调节
  • 批准号:
    7918175
  • 财政年份:
    2001
  • 资助金额:
    $ 39.71万
  • 项目类别:
Physiologic Regulation of Hematopoiesis by Notch
Notch对造血的生理调节
  • 批准号:
    6395391
  • 财政年份:
    2001
  • 资助金额:
    $ 39.71万
  • 项目类别:
Physiologic Regulation of Hematopoiesis by Notch
Notch对造血的生理调节
  • 批准号:
    7485362
  • 财政年份:
    2001
  • 资助金额:
    $ 39.71万
  • 项目类别:

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    1980
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DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
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