Dynamic gene networks in human cells exposed to ionizing radiation.

描述（由申请人提供）：人类通过环境和医疗干预暴露于电离辐射，但我们对人体细胞科普电离辐射引起的生理应激的机制知之甚少。虽然许多研究已经检查了人类细胞暴露于电离辐射后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述哪些基因相互作用以协调细胞对电离辐射的反应。在这项研究中，我们将研究动态基因调控网络动员细胞响应电离辐射。我们将通过在照射前和照射后不同时间点分析正常人B细胞系中人基因的基因表达来做到这一点。我们将以允许在不同时间点鉴定基因-基因相互作用的方式分析数据。通过检查来自无关个体以及家族的细胞系，我们将：（1）推断基因-基因相互作用对电离辐射的反应，（2）识别和比较基线和暴露于电离辐射后不同时间点的基因-基因相互作用网络，以及（3）通过整合我们实验室进行的遗传研究结果来识别基因之间的调控关系。 公共卫生相关性：人类在各种环境中暴露于电离辐射（例如环境中的氡，医用X射线），有些人会产生严重的不良反应（例如癌症）。对电离辐射的细胞反应的系统水平的理解将使我们能够（1）了解电离辐射的环境暴露如何影响人类，（2）产生关于为什么个体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.