Myeloid reprogramming in response to acute radiation tissue damage

响应急性辐射组织损伤的骨髓重编程

基本信息

  • 批准号:
    10375367
  • 负责人:
  • 金额:
    $ 34.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-03-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

We have discovered the striking emergence of a novel subpopulation of myeloid cells after whole body and local irradiation that expresses both granulocytic (Ly6G) and monocytic (Ly6C) lineage markers at high levels. This immature phenotype is not normally evident in peripheral organs at baseline but is mobilized from bone marrow myeloerythroid progenitor cells. Their phenotype suggests that they may be granulocyte-derived myeloid suppressor cells, as does their co-expression of PDL-1, PD-1, and CD39. We hypothesize that they are an endogenous mechanism to minimize collateral damage from radiation-induced tissue damage and inflammation. Importantly, depletion of this subset increases vulnerability to hematopoietic acute radiation syndrome in mice and obliterates the action of radiation mitigator drugs that we have tested. Our goal is to illuminate the fate and function of these myeloid cells and the role they play in acute and chronic radiation tissue damage in animal models. We are mindful that myeloid cells tend to be exquisitely sensitive to rapidly changing environments and that their phenotype and function adapt accordingly; in keeping with the plasticity that is a hallmark of this lineage. Our hypothesis is that these cells sense and respond to damage- associated molecules and cytokines released in the aftermath of radiation exposure, that they feed back to the bone marrow driving self-sustaining loops of inflammation and myeloid lineage reprogramming which skews the immune balance away from lymphopoiesis and towards myelopoiesis. In the long term, persistent myeloid skewing affects hematopoiesis and perhaps function of other organs. The most likely culprit for mediating this rapid radiation-induced myeloid surge is IL-6, but other factors are probably important. We will pursue these avenues using a tool box of multi-color flow cytometry, Ly6G-depleting antibody, adoptive cell transfer and loss of function genetic mouse models that will allow us to finely dissect the role of this response in acute and late radiation damage. As part of the study, we will verify if these cells have inherent radiation mitigating capabilities. Finally, these cells persist systemically and probably contribute to delayed normal tissue and tumor responses to radiation therapy. We will therefore determine how they might shape persistent inflammatory states and immune dysfunction. With these studies we hope to gain a deeper understanding of the interactions between radiation tissue damage, immune responses and the recovery processes with the ultimate goal of reprogramming the myeloid system to better aid balanced normal tissue recovery after localized and whole body radiation exposures.
我们已经发现了一个新的髓样细胞亚群的惊人出现后,整个身体, 局部照射,以高水平表达粒细胞(Ly 6 G)和单核细胞(Ly 6C)谱系标志物。 这种不成熟的表型在基线时的外周器官中通常不明显,但从骨中动员出来 骨髓红系祖细胞它们的表型表明它们可能是粒细胞来源的 骨髓抑制细胞,如它们的PDL-1、PD-1和CD 39的共表达。我们假设他们 是一种内源性机制,可最大限度地减少辐射诱导组织损伤的附带损伤, 炎症重要的是,这一亚群的耗竭增加了造血急性辐射的脆弱性 综合征的小鼠和抹杀的辐射缓解药物的作用,我们已经测试。 我们的目标是阐明这些骨髓细胞的命运和功能,以及它们在急性和慢性疾病中所起的作用。 放射性组织损伤的动物模型。我们注意到,骨髓细胞往往对 快速变化的环境,其表型和功能也相应地适应; 可塑性是这一血统的标志。我们的假设是这些细胞感知并对损伤做出反应- 辐射暴露后释放的相关分子和细胞因子,它们反馈给细胞 骨髓驱动自我维持的炎症循环和髓系重编程, 免疫平衡从淋巴细胞生成转向骨髓细胞生成。从长远来看,持续性骨髓 偏斜影响造血,可能还影响其他器官的功能。最有可能的罪魁祸首是 快速辐射诱导的骨髓激增是IL-6,但其他因素可能也很重要。我们将继续努力, 使用多色流式细胞术、Ly 6 G耗竭抗体、过继细胞转移和丢失工具箱的途径 功能遗传小鼠模型,这将使我们能够精细地剖析这种反应在急性和晚期的作用, 辐射损伤作为研究的一部分,我们将验证这些细胞是否具有固有的辐射缓解功能, 能力的最后,这些细胞持续全身,并可能有助于延迟正常组织, 肿瘤对放射治疗的反应因此,我们将确定它们如何塑造持久性 炎症状态和免疫功能障碍。 通过这些研究,我们希望能够更深入地了解辐射组织之间的相互作用 损伤,免疫反应和恢复过程,最终目标是重新编程骨髓 系统,以更好地帮助平衡的正常组织恢复后,局部和全身辐射照射。

项目成果

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Dorthe Schaue其他文献

Dorthe Schaue的其他文献

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{{ truncateString('Dorthe Schaue', 18)}}的其他基金

Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
  • 批准号:
    10088403
  • 财政年份:
    2020
  • 资助金额:
    $ 34.97万
  • 项目类别:
Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
  • 批准号:
    10557205
  • 财政年份:
    2020
  • 资助金额:
    $ 34.97万
  • 项目类别:
Acute radiation injury alters microRNA profiles that predict late tissue-specific damage
急性辐射损伤改变了预测晚期组织特异性损伤的 microRNA 谱
  • 批准号:
    10329926
  • 财政年份:
    2020
  • 资助金额:
    $ 34.97万
  • 项目类别:
Myeloid reprogramming in response to acute radiation tissue damage
响应急性辐射组织损伤的骨髓重编程
  • 批准号:
    10112746
  • 财政年份:
    2019
  • 资助金额:
    $ 34.97万
  • 项目类别:
Visualizing radiation-induced tumor immune responses
可视化辐射诱导的肿瘤免疫反应
  • 批准号:
    9908059
  • 财政年份:
    2019
  • 资助金额:
    $ 34.97万
  • 项目类别:
Myeloid reprogramming in response to acute radiation tissue damage
响应急性辐射组织损伤的骨髓重编程
  • 批准号:
    10583509
  • 财政年份:
    2019
  • 资助金额:
    $ 34.97万
  • 项目类别:
Radiotherapy-induced tumor immunity
放射治疗诱导的肿瘤免疫
  • 批准号:
    9323354
  • 财政年份:
    2015
  • 资助金额:
    $ 34.97万
  • 项目类别:
Radiotherapy-induced tumor immunity
放射治疗诱导的肿瘤免疫
  • 批准号:
    8963306
  • 财政年份:
    2015
  • 资助金额:
    $ 34.97万
  • 项目类别:

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