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

基本信息

  • 批准号:
    10557205
  • 负责人:
  • 金额:
    $ 40.17万
  • 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:
    2020-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Despite extensive investigations into the effects of radiation on normal tissues, there is currently no easy way to quickly determine if a person has been exposed to radiation, to what dose and type, and if they are likely to suffer serious acute or delayed consequences. Time may also be of the essence for triaging large numbers of individuals and with that in mind have developed a robust infrastructure for the discovery and development of a novel biodosimeter that offers a compelling solution; namely circulating microRNA (miRNA) profiling. It is based on our extensive experience in studying survivors of acute radiation syndromes (ARS) in murine and non-human primate models, and our understanding of the road toward the development of delayed effects, which don’t follow the same strict time-dose constraints as ARS. Instead, they display common patterns of inflammation and aberrant immune engagement, leading to late tissue toxicity and premature death. Our hypothesis is that radiation-induced systemic myeloid cell mobilization and immunohematopoietic imbalance drive late radiation damage that, remarkably, occurs only in some mice and not in others. We have compelling evidence that dynamic events at the irradiated tissue-immune interface are reflected in a measurable shift in the circulating miRNAs landscape suggesting that they 1) go hand-in-hand with the initial radiation insult and 2) precede late tissue-specific radiation-induced toxicities such as fibrosis in heart and lung. Against this backdrop we propose to develop a panel of miRNAs and build a comprehensive biomarker platform that integrates signals from both acute and late radiation damage. Our goal is to extend our existing knowledge from low LET exposures and determine if known patterns of miRNA changes are inherently different for radiation of different qualities, and if the nature of the associated tissue damage also changes. In Aim 1 we will determine broad parameters such as dose-rate and time that define radiation-induced tissue damage in the aftermath of hematopoietic ARS caused by X-rays versus neutron exposures. We will rely on proven, robust endpoints such clinical examination, blood work and necropsy amongst other, more tissue specific readouts to capture multi-organ disease. Longitudinal plasma miRNA profiles will be generated for each mouse as part of Aim 2 and aligned within the context of tissue damage to identify putative biomarker candidates to achieve our ultimate goal and build a biomarker panel for tissue- and radiation-specific damage (Aim 3). The study has broad relevance to acute and chronic radiation effects and it epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis. We are mindful of the challenges that arise when comparing X-rays with neutrons using in vivo irradiation and the complexities that are inherent in studying late morbidities. We therefore assembled a team that combines expertise in radiation biology, immunology, miRNA profiling, radiation physics and dosimetry, veterinary care and statistics to cover all aspects of this research.
项目总结

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:
    $ 40.17万
  • 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:
    $ 40.17万
  • 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:
    $ 40.17万
  • 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:
    $ 40.17万
  • 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:
    $ 40.17万
  • 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:
    10375367
  • 财政年份:
    2019
  • 资助金额:
    $ 40.17万
  • 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:
    $ 40.17万
  • 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:
    $ 40.17万
  • 项目类别:

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