PA-12-149: Research Supplements to Promote Diversity in Health-Related Research (Admin Supp): Metabolomic biomarkers and instrumentation for assessment of radiation injury,

PA-12-149:促进健康相关研究多样性的研究补充(管理补充):用于评估辐射损伤的代谢组生物标志物和仪器,

基本信息

  • 批准号:
    8991790
  • 负责人:
  • 金额:
    $ 6.02万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-05-24 至 2018-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This proposal combines our metabolomics and radiation-signaling expertise with the expertise of team members in instrumentation for rapid and cost-effective assessment of select metabolites. The overall goals are to develop a reliable database of radiation metabolomic biomarkers in humans from easily-accessible biofluids, and then to refine subset(s) that will allow assessment of select biomarkers with instrumentation that could provide the basis for application in clinical and potentially in-field scenarios. The propose study builds on an extensive track record of accomplishments in radiation metabolomics, as well as the use of approaches, particularly differential mobility spectrometry (DMS), that allows for high-throughput assessment of metabolite biomarkers of interest. In the case of radiation metabolomics, our laboratory and its collaborators have made major contributions in establishing this field using a modern liquid chromatography (LC) mass spectrometry (MS) approach in a variety of animal models as well as in human cells. We have shown in publications over the last several years that they are dose-dependent and timecourse-dependent responses in urine metabolomics profiles after doses of ionizing radiation (IR) that are a NIAID priority. Recently, we have shown that there is evidence for specificity in the IR response in vivo compared to another relevant stressor, which mimics the inflammatory response to sepsis. Our team has also published extensively on the development and refinement of DMS, which should allow for selective "tuning" for metabolite biomarkers without cumbersome LC. We have demonstrated that DMS allows isolation of select metabolites so that they can then be detected with a simplified and miniature MS system. In the case of human biomarker development, we have a collection of biofluids from a large number of patients undergoing total body irradiation (TBI) and have already demonstrated significant metabolomic responses in urine after TBI. Aim 1 will be to develop a robust metabolomic biomarker database for human exposure using our high-end laboratory LCMS approach. Since dose and timecourse sampling is limited in TBI patients, we will use our extensive on-going mouse model datasets, which are funded by a different mechanism, as well as non-human primate samples provided by collaborators to model a much wider range of exposures. In the case of radiation toxicity, we have exciting preliminary data demonstrating that toxicity and lethality, which occurs approximately 2 wk after irradiation, can be distinguished as early as 1 day after irradiation in mice. Aim 2 will develop biomarker panels to distinguish IR biomarker signatures from other injury and disease processes. A modern bioinformatics pipeline, which includes novel in-house algorithms, has been developed to facilitate biomarker discovery. Having developed a robust IR dataset, we will then focus in aim 3 on development of convenient and cost-effective instrumentation that can provide the basis for use in clinical and ultimately in-field scenarios, and refine subsets of IR biomarkers that can be effectively measured with our approaches such as DMS-MS.
描述(由申请人提供):该提案将我们的代谢组学和辐射信号专业知识与团队成员在仪器方面的专业知识相结合,以快速和经济有效地评估选定的代谢物。总体目标是从易于获得的生物流体中开发人体辐射代谢组学生物标志物的可靠数据库,然后改进子集,以允许使用仪器评估选择的生物标志物,这些仪器可以为临床和潜在的现场场景中的应用提供基础。这项研究建立在辐射代谢组学成就的广泛记录,以及方法的使用,特别是差分迁移率光谱法(DMS),允许对感兴趣的代谢物生物标志物进行高通量评估。在辐射代谢组学的情况下,我们的实验室及其合作者在建立这一领域作出了重大贡献,使用现代液相色谱(LC)质谱(MS)方法在各种动物模型以及人类细胞。我们在过去几年的出版物中表明,在NIAID优先考虑的电离辐射(IR)剂量后,尿液代谢组学特征中的反应具有剂量依赖性和时间依赖性。最近,我们已经表明,有证据表明,在体内的IR反应的特异性相比,另一个相关的应激源,模拟脓毒症的炎症反应。我们的团队还发表了大量关于DMS的开发和改进的文章,这应该允许对代谢物生物标志物进行选择性“调整”,而无需繁琐的LC。我们已经证明,DMS允许选择代谢物的隔离,使他们可以用一个简化的和微型MS系统检测。在人类生物标志物开发的情况下,我们收集了大量接受全身照射(TBI)的患者的生物流体,并且已经证明了TBI后尿液中的显著代谢组学反应。目标1将是使用我们的高端实验室LCMS方法开发一个强大的人体暴露代谢组学生物标志物数据库。由于TBI患者的剂量和时间过程采样有限,我们将使用我们广泛的正在进行的小鼠模型数据集,这些数据集由不同的机制资助,以及合作者提供的非人灵长类动物样本来模拟更广泛的暴露范围。在辐射毒性的情况下,我们有令人兴奋的初步数据表明,毒性和致死性,这发生在照射后约2周,可以区分早在照射后1天的小鼠。目标2将开发生物标志物面板,以区分IR生物标志物签名与其他损伤和疾病过程。现代生物信息学管道,其中包括新的内部算法,已被开发,以促进生物标志物的发现。在开发了一个强大的IR数据集之后,我们将专注于目标3,开发方便且具有成本效益的仪器,这些仪器可以为临床和最终现场场景的使用提供基础,并改进可以使用我们的方法(如DMS-MS)有效测量的IR生物标志物的子集。

项目成果

期刊论文数量(0)
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Albert J Fornace其他文献

Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress
p53 在生长停滞和凋亡中的作用:在基因毒性应激后刹车
  • DOI:
    10.1038/sj.onc.1202576
  • 发表时间:
    1999-01-12
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Sally A Amundson;Timothy G Myers;Albert J Fornace
  • 通讯作者:
    Albert J Fornace
Role of p21Waf1/Cip1/Sdi1 in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells
使用四环素诱导系统在 p53 缺陷细胞中研究 p21Waf1/Cip1/Sdi1 在细胞死亡和 DNA 修复中的作用
  • DOI:
    10.1038/sj.onc.1201004
  • 发表时间:
    1997-04-17
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    M Saeed Sheikh;Yong Q Chen;Martin L Smith;Albert J Fornace
  • 通讯作者:
    Albert J Fornace
Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a
基因组不稳定性、中心体扩增、细胞周期检查点和 Gadd45a
  • DOI:
    10.1038/sj.onc.1205774
  • 发表时间:
    2002-09-09
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    M Christine Hollander;Albert J Fornace
  • 通讯作者:
    Albert J Fornace
Regulation of translation initiation following stress
应激后翻译起始的调控
  • DOI:
    10.1038/sj.onc.1203131
  • 发表时间:
    1999-11-04
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    M Saeed Sheikh;Albert J Fornace
  • 通讯作者:
    Albert J Fornace
Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC<sup>1638N/+</sup> mice
  • DOI:
    10.1016/j.lssr.2017.04.003
  • 发表时间:
    2017-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Shubhankar Suman;Santosh Kumar;Bo-Hyun Moon;Albert J Fornace;Kamal Datta
  • 通讯作者:
    Kamal Datta

Albert J Fornace的其他文献

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{{ truncateString('Albert J Fornace', 18)}}的其他基金

Metabolic impairment plays a critical role in radiation-induced T cell immune dysfunction
代谢损伤在辐射诱导的 T 细胞免疫功能障碍中起着关键作用
  • 批准号:
    10474738
  • 财政年份:
    2022
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolic impairment plays a critical role in radiation-induced T cell immune dysfunction
代谢损伤在辐射诱导的 T 细胞免疫功能障碍中起着关键作用
  • 批准号:
    10668368
  • 财政年份:
    2022
  • 资助金额:
    $ 6.02万
  • 项目类别:
Enhancing cancer treatment by normal tissue protection
通过保护正常组织增强癌症治疗
  • 批准号:
    9452919
  • 财政年份:
    2014
  • 资助金额:
    $ 6.02万
  • 项目类别:
Enhancing cancer treatment by normal tissue protection
通过保护正常组织增强癌症治疗
  • 批准号:
    9207750
  • 财政年份:
    2014
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolomic biomarkers and instrumentation for assessment of radiation injury
用于评估辐射损伤的代谢组生物标志物和仪器
  • 批准号:
    8650260
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolomic biomarkers and instrumentation for assessment of radiation injury
用于评估辐射损伤的代谢组生物标志物和仪器
  • 批准号:
    8369729
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolomic biomarkers and instrumentation for assessment of radiation injury
用于评估辐射损伤的代谢组生物标志物和仪器
  • 批准号:
    9054771
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolomic biomarkers and instrumentation for assessment of radiation injury
用于评估辐射损伤的代谢组生物标志物和仪器
  • 批准号:
    8473783
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
Metabolomic biomarkers and instrumentation for assessment of radiation injury
用于评估辐射损伤的代谢组生物标志物和仪器
  • 批准号:
    8839195
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
X-irradiator for in vivo and in vitro studies with relevance to basic stress sign
用于与基本应激体征相关的体内和体外研究的 X 射线辐射器
  • 批准号:
    7794276
  • 财政年份:
    2010
  • 资助金额:
    $ 6.02万
  • 项目类别:

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