Dynamic gene networks in human cells exposed to ionizing radiation.

描述(申请人提供)：人类通过环境和医学干预暴露在电离辐射中，但我们对人类细胞应对电离辐射引起的生理压力的机制知之甚少。虽然许多研究检查了人类细胞暴露在电离辐射下时诱导的基因表达的变化，但我们缺乏一个全面的系统水平的观点来描绘哪些基因相互作用来协调细胞对电离辐射的反应。在这项研究中，我们将研究细胞对电离辐射的反应所动员的动态基因调控网络。为此，我们将通过分析照射前和照射后不同时间点正常人类B细胞系中人类基因的表达来实现这一点。我们将以一种允许识别不同时间点的基因-基因相互作用的方式来分析数据。通过检测来自无关个体和家庭的细胞系，我们将：(1)推断对电离辐射的响应改变的基因-基因相互作用；(2)识别和比较在基线和暴露于电离辐射后的不同时间点的基因-基因相互作用网络；(3)通过整合我们实验室进行的遗传学研究的结果，确定基因之间的调控关系。 与公共健康相关：人类在各种环境中暴露于电离辐射(例如环境中的氡、医疗X光)，有些人会出现严重的不良反应(例如癌症)。对电离辐射的细胞反应的系统水平的了解将使我们能够(1)了解环境暴露于电离辐射可能会如何影响人类，(2)产生关于为什么个人对电离辐射的反应不同的假设，以及(3)确定我们可以做些什么来调节这种反应。

DESCRIPTION (provided by applicant): Humans are exposed to ionizing radiation via the environment and through medical interventions, but we know relatively little about the mechanisms by which human cells cope with the physiological stress caused by ionizing radiation. While many studies have examined changes in gene expression that are induced upon exposure of human cells to ionizing radiation, we lack a comprehensive systems-level view delineating which genes interact to coordinate a cellular response to ionizing radiation. In this study, we will examine the dynamic gene regulatory networks mobilized by cells in response to ionizing radiation. We will do so by profiling gene expression of human genes in normal human B cell lines before and at various time points after irradiation. We will analyze the data in a way that permits the identification of gene-gene interactions at various time points. By examining cell lines from unrelated individuals as well as families, we will: (1) infer gene-gene interactions that change in response to ionizing radiation, (2) identify and compare networks of gene-gene interactions at baseline and at various times points after exposure to ionizing radiation, and (3) identify regulatory relationships between genes by integrating results from genetic studies performed in our lab. PUBLIC HEALTH RELEVANCE: Humans are exposed to ionizing radiation in a variety of settings (e.g. radon in the environment, medical x-rays), with some having severe adverse reactions (e.g. cancer). A much needed systems-level understanding of the cellular response to ionizing radiation will allow us to (1) understand how environmental exposures to ionizing radiation may affect humans, (2) generate hypotheses as to why individuals respond differently to ionizing radiation, and (3) determine what we can do to modulate this response.