Rapid Automated High-Throughput Radiation Biodosimetry

快速自动化高通量辐射生物剂量测定

• 批准号: 8308609
• 负责人: DAVID JONATHAN BRENNER
• 金额: $ 72.84万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8308609
• 关键词: Accounting; Acute; Address; Animal Organ; Automation; Biological Assay; Biological Markers; Blood; Blood specimen; Body part; Cancer Patient; Cell division; Cessation of life; Chromosome Deletion; Chromosome abnormality; Complex; DNA Damage; DNA Repair; Data; Development; Devices; Dose; Dose-Rate; Ear; Erythema; Event; Explosion; Exposure to; Fast Neutrons; Gamma Rays; Goals; Hematopoietic; Hour; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Individual; Investigation; Kinetics; Lead; Lethal Dose 50; Link; Lymphocyte; Measurement; Measures; Micronucleus Tests; Mind; Modification; Mononuclear; Mouse Strains; Mus; Nature; Neutrons; Nuclear; Organ; Performance; Photons; Population; Positioning Attribute; Radiation; Radiation Injuries; Radiation Tolerance; Radiation therapy; Radioactive; Radioisotopes; Readiness; Relative Biological Effectiveness; Research; Residual state; Running; Sampling; Security; Series; Signal Transduction; Simulate; System; Techniques; Time; Triage; Uncertainty; Woman; Work; base; biodosimetry; breast lumpectomy; carcinogenesis; dirty bomb; high throughput screening; in vivo; interest; irradiation; malignant breast neoplasm; man; micronucleus; minimally invasive; reconstruction; repaired; response; statistics; tool

Our overriding theme is ultra high-throughput radiation biodosimetry. It is well established that this is a central and necessary component of any effective response to a large scale radiological event. The RABIT (Rapid Automated Biodosimetry Tool) system developed to date in Project 1 has a current throughput of 6,000 samples / day, and a projected (2010) throughput of 30,000 samples / day. These throughputs were achieved by complete robotically-based automation of standard micronucleus and Y-H2AX assays. One first main renewal theme, "Beyond Simple Exposures", is to assess the significance of various realistic radiation event scenarios, in particular protraction of radiation exposure, partial-body exposure, internal emitters, and neutron exposure. Our goal is to understand the responses of the standard RABIT assays to these types of exposures, and quantify the uncertainties associated with dose reconstruction in these scenarios. The assays will be done both with irradiated mice and with ex-vivo irradiated human blood, with the unique irradiation facilities of the Irradiation Core, allowing sample sharing with the other two Projects. While the micronucleus assay has high throughput and excellent post-irradiation stability, its assay time is ~3 days, due to the need to stimulate cell division in vitro. We have preliminary evidence of the practicality of a micronucleus assay using /T?ononi;c/ear lymphocytes, which have already divided in vivo. Our second theme is to develop and assess this system which, with full automation, would reduce the assay time to ~3 hrs Having developed high-throughput systems using various biomarkers for biodosimetry, we are in a unique position to probe the application of these high-throughput biomarkers for predicting inter-individual sensitivity to acute radiation injury. Thus our final renewal theme is "Beyond Dose: Towards Individual Radiosensitivity". The six high-throughput automated RABIT endpoints that we will use are baseline micronuclei, ex-vivo radiation-induced micronuclei, ex-vivo radiation-induced y-H2AX, ex-vivo radiation-induced chromosomal deletions, DNA damage repair kinetics (with Y-H2AX, ATM, 53BP1, and Mdcl foci), and residual damage after 24 h. The practical use of this number of assays is made possible by their being fully automated within the RABIT. Studies will be done with inbred mice with differing acute radiosensitivities, and by assessing associations between these endpoints and acute erythema in 500 irradiated breast cancer patients.

我们的压倒性主题是超高通量辐射生物测量法。众所周知，这是 对大规模放射学事件的任何有效响应的中心和必要组成部分。兔子 （快速自动化生物测量工具）迄今为止在项目1中开发的系统具有当前的吞吐量 每天6,000个样本，预计（2010年）每天30,000个样品的吞吐量。这些吞吐量是 通过完全基于机器人的标准微核和Y-H2AX分析来实现。 第一个主要续订主题“超越简单暴露”是评估各种现实的重要性 辐射事件方案，特别是辐射暴露，部分体体暴露的突出，内部 发射器和中子暴露。我们的目标是了解标准Rabit分析的响应 这些类型的暴露，并量化与剂量重建相关的不确定性 方案。这些测定将通过辐照小鼠和外部辐照的人类血液进行，并与 辐射核心的独特辐照设施，允许与其他两个项目进行样品共享。 虽然微核测定法具有较高的吞吐量和出色的辐照后稳定性，但其测定时间为 〜3天，由于需要在体外​​刺激细胞分裂。我们有初步证据表明 使用 /t？ononi; c /ear淋巴细胞的微核测定法，该测定已在体内分裂。我们的第二个 主题是开发和评估该系统，通过完全自动化，将测定时间减少到3小时 在使用各种生物标志物进行生物测量法开发了高通量系统之后，我们处于独特之处 探测这些高通量生物标志物用于预测个体敏感性的位置 急性辐射损伤。因此，我们的最终更新主题是“超越剂量：迈向单个放射敏感性”。 我们将使用的六个高通量自动化兔终点是基线微核 辐射诱导的微核，前体辐射诱导的Y-H2AX，EX-VIVO诱导的染色体 删除，DNA损伤维修动力学（带有Y-H2AX，ATM，53BP1和MDCL焦点）以及残留损害 24小时后。通过在其中完全自动化的这种测定数量的实际使用可以使 兔子。将对具有不同急性放射敏性的近交小鼠进行研究，并通过评估 这些终点与500名辐照乳腺癌患者的急性红斑之间的关联。