Center for High-Throughput Minimally-Invasive Radiation Biodosimetry

描述(由申请人提供)：这一整体CMCR计划代表了一种凝聚力很强的多学科方法，以实现高度集中的目标：高通量生物剂量测定及其在辐射诱导损伤的个体化早期预测中的应用。哥伦比亚大学CMCR计划的一个主要特点仍然是关注三种不同的高通量方法：全自动细胞遗传学(项目1)、功能基因组学(项目2)和代谢组学(项目3)。这些不同的方法代表了一系列风险-收益平衡，追求这三种方法对每个人都有协同效益，不仅在共同的实验设计和样本共享方面，而且在相互比较和解释结果及其实际意义方面。这三个项目由四个综合科学核心支持，每个项目都有相同的共同主题：1.实现复杂暴露的高通量生物剂量学：目标是评估不同的暴露情景，特别是不同的剂量率、内部发射器和中子暴露如何调节生物标记物的反应，以及调查唯一反映不同暴露情景存在的生物标志物。2.走向高通量放射敏感性/迟发性损伤的个体化预测指标：转录组学和代谢组学方法已被证明在预测个体化辐射诱导的急性效应方面具有实用价值，这一概念将扩展到迟发性效应。项目1的重点是放射治疗患者的肺炎与体外血液照射后高通量DNA损伤终点之间的潜在相关性。项目2和3的重点是转录和代谢生物标记物，用于早期预测小鼠肺死亡的个体化。根据个人敏感性这一主题，计划对炎症性疾病的重要性进行研究，并将预测性分析作为辐射缓解剂开发的辅助手段，作为缓释剂有效性的早期指标。3.技术开发：目标是利用商业高通量筛查技术，用于基于细胞的筛查、转录和质谱学，这些技术在大学和工业环境中越来越多地可用。新的化验方案和“前端”样本采集系统将利用这些常见的设备。进一步的技术开发是一种廉价的持续降低剂量率的137Cs辐照器，它可以模拟由137Cs内部照射引起的任何随时间减少的剂量率；该设备可以为CMCR 137Cs内部发射器的研究提供主要刺激。将保持高度统一的组织结构。在最高级别监督科学计划的是外部科学咨询小组(ESAG)，其成员每年都会亲自开会。内部咨询委员会(IAC)负责整个CMCR方案的地方协调。ESAG和IAC之间的互动一直是该计划科学方向的核心。

DESCRIPTION (provided by applicant): This overall CMCR program represents a cohesive multidisciplinary approach to highly focused goals: High-throughput biodosimetry and its application to individualized early prediction of radiation-induced injury. A central characteristi of the Columbia CMCR program remains a focus on three different high-throughput approaches: fully-automated cytogenetics (Project 1), functional genomics (Project 2), and metabolomics (Project 3). These different approaches represent a range of risk-benefit balances, and pursuing all three is of synergetic benefit to each, not only in terms of common experimental design and sample sharing, but also in terms of intercomparing and interpreting the results and their practical significance. The three Projects, supported by four integrated scientific Cores, each share the same common themes: 1. Towards High-Throughput Biodosimetry for Complex Exposures: The goal is to assess how different exposure scenarios, in particular different dose rates, internal emitters, and neutron exposure, modulate biomarker response, as well as investigating biomarkers that uniquely reflect the presence of different exposure scenarios. 2. Towards High-Throughput Individualized Predictors of Radiosensitivity / Late Injury: Transcriptomics and metabolomics approaches have been shown here to have utility for predicting individualized radiation-induced acute effects, and this concept will be extended toward late effects. The Project 1 focus is on potential correlations between pneumonitis in radiotherapy patients and high-throughput DNA damage endpoints after ex-vivo blood irradiation. The Project 2 and 3 focus is on transcriptomic and metabolomic biomarkers for individualized early prediction of pulmonary lethality in mice. In keeping with the theme of individual sensitivity, studies are planned of the significance of inflammatory diseases, as well as of predictive assays as an adjunct to radiation mitigator development, as early indicators of mitigator effectiveness. 3. Technology Development: The goal is to take advantage of commercial high-throughput screening technologies, for cell-based screening, transcriptomics, and mass spectrometry, which are increasingly available in university and industry settings. New assay protocols and "front-end" sample acquisition systems will take advantage of these common devices. A further technology development is an inexpensive continuously-decreasing-dose-rate 137Cs irradiator, simulating any time-decreasing dose rate caused by internal 137Cs exposure; the device can provide a major stimulus to CMCR 137Cs internal-emitter studies. A highly unified organizational structure will be maintained. Overseeing the scientific program at the highest level is the External Scientific Advisory Group (ESAG), whose members meet in person annually. The Internal Advisory Committee (IAC) has responsibility for local coordination of the entire CMCR Program. The interactions between the ESAG and the IAC have been central to the Program's scientific direction.