Core--Functional genomics

现在已经确定，人类细胞暴露于环境压力，包括电离辐射，激活多种信号转导途径，导致基因表达变化的复杂模式。特定基因的表达可以是剂量依赖性和应力依赖性的，使得基因表达谱分析成为急需的辐射生物剂量测定的潜在信息方法。然而，仍有几个问题有待解决，包括在基线和治疗的表达水平的变化，人群中，潜在的混杂效应，并确定一个最佳的信息基因集。循环淋巴细胞是早期辐射损伤的敏感靶点，在诱导的基因表达变化方面具有高度反应性，并且相对容易进行活检。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。该核心将1）建立和完善诊断人类辐射暴露的基因表达特征 2）与微核（项目1）和患者尿液代谢组学（项目3）平行评估基因表达，以直接比较生物剂量测定技术，以及3）提供资源，用于监督与功能基因组学相关的实验设计，并根据需要培训工作人员，以支持项目3和试点项目。 通过在一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一种有效的筛选潜在的信息辐射生物标志物，但也可以提供洞察人类对早期辐射损伤的反应的机制基础。这样的信息可能会建议其他生物剂量测定技术的改进，并促进未来的合作中心之间的高通量微创辐射生物剂量测定和其他中心的医疗对策辐射，例如，建议“药物靶点”和机会的化学保护干预策略的发展。

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.