Core--Functional genomics

现已证实，人类细胞暴露于环境应激，包括电离辐射，激活多个信号转导途径，导致基因表达变化的复杂模式。特定基因的表达可能是剂量和压力相关的，这使得基因表达谱成为急需的辐射生物剂量测定的潜在信息量方法。然而，仍有几个问题需要解决，包括群体中基线和处理后表达水平的变化，潜在的混杂效应，以及最佳信息基因集的识别。循环淋巴细胞是早期辐射损伤的敏感靶点，在诱导基因表达变化方面具有很高的响应性，并且相对容易活检。因此，外周血细胞将是我们开发用于辐射暴露的基因表达生物剂量计的主要模型。这个核心将1)建立和提炼诊断人类辐射暴露的基因表达特征 2)在微核(项目1)和患者尿液代谢组学(项目3)的同时评估基因表达，以便能够直接比较生物剂量学技术；以及3)提供资源，监督与功能基因组学有关的实验设计，并根据需要培训支持项目3和试点项目的工作人员。 通过允许在单个实验中测量几乎整个基因组的基因表达变化，现代长寡核苷酸微阵列方法不仅是对潜在信息的辐射生物标志物的有效筛选，而且还可能提供对人类对早期辐射损伤反应的机制基础的洞察。这些信息可能会提示其他生物剂量学技术的改进，并促进高通量微创辐射生物剂量学中心与其他辐射医学对策中心之间的未来合作，例如通过建议“可用药靶点”和开发化学防护干预策略的机会。

It is now well established that exposure of human cells to environmental stresses, including ionizing radiation, activates multiple signal transduction pathways, resulting in complex patterns of gene expression change. Expression of specific genes can be both dose- and stress- dependent, making gene expression profiling a potentially informative approach for much-needed radiation biodosimetry. Several issues remain to be resolved, however, including variations in baseline and treated expression levels among the population, potential confounding effects, and identification of an optimally informative gene set. Circulating lymphocytes represent a sensitive target for early radiation injury, highly responsive in terms of induced gene expression changes, and relatively easily biopsied. Peripheral blood cells will therefore be our primary model for development of a gene expression biodosirneter for radiation exposure. This Core will 1) establish and refine gene expression signatures diagnostic of human radiation exposure and dose in support of Project 2, 2) assess gene expression in parallel with micronuclei (Project 1) and patient urinary metabolomics (Project 3) to enable direct comparisons of biodosimetric techniques, and 3) provide a resource for oversight of experimental design pertaining to functional genomics and training of staff in support of Project 3 and the Pilot Projects as needed. By allowing measurement of gene expression changes across virtually the entire genome in a single experiment, the modern long oligonucleotide microarray approach is not only an efficient screen for potentially informative radiation biomarkers, but may also provide insight into the mechanistic basis of the human response to early radiation injury. Such information may suggest refinements of other biodosimetry techniques, and facilitate future collaborations between the Center for High-Throughput Minimally-Invasive Radiation Biodosimetry and the other Centers for Medical Countermeasures against Radiation, for instance by suggesting "druggable targets" and opportunities for development of chemoprotective intervention strategies.