Organ-specific NRF2-mediated protein signatures of radiation exposure & tissue da

描述(由申请人提供)：这项建议的总体合理性是为暴露于电离辐射(IR)中的个人开发一种血液测试，以提供暴露和暴露相关器官损害的个人分子签名，用于指导治疗方案，并可能用于反馈治疗效果。我们将进行假设驱动的靶向蛋白质组学实验，重点研究NRF2介导的小鼠对IR的反应。这些实验将针对不同年龄和性别的一系列小鼠品系，并将调查靶向器官IR暴露。之所以选择NRF2介导的反应蛋白，是因为我们之前的研究表明，2-8Gy单剂量电离辐射以剂量依赖的方式激活乳腺癌细胞中抗氧化反应元件(ARE)依赖的转录(通过NRF2)，但只有在延迟一天或更长时间后才能激活。起病晚和寿命长的反应对于预期的生物标记物Rational特别有用。我们的初步实验将集中在IR暴露小鼠的器官和浓缩的血液亚组分，以提供一组潜在的组织特异性生物标记物，用于随后研究它们在血浆中的特定存在。因此，我们的实验将解决三个一般假设；有一些NRF2调制的蛋白质将在组织中以剂量依赖的方式变化，以响应IR；损伤模式将提供分子签名，报告总体辐射暴露的严重程度，以及特定的单个器官应激/损伤；以及这些潜在的生物标记物中的一些将泄漏到血流中并持续存在，以便它们可以在血浆中进行测量，以便进行人体血液测试。虽然我们的实验专注于IR剂量依赖的反应，但我们注意到，通过针对个别器官的应激蛋白，我们可能会找到报告个人健康/痛苦的生物标记物，而不考虑剂量，从而适应具有异常敏感性的个人。 公共卫生相关性：这项建议的总体合理性是为暴露在电离辐射(IR)中的个人开发一种血液测试，以提供暴露和暴露相关器官损害的个人分子签名，用于指导治疗方案，并可能用于反馈治疗效果。这项拟议的工作集中在暴露于IR的小鼠不同器官中参与IR延迟抗氧化反应的蛋白质，并将测试这些蛋白质在血液中的存在。这些实验将针对不同年龄和性别的一系列小鼠品系，并将调查靶向器官IR暴露。

DESCRIPTION (provided by applicant): The overall rational of this proposal is to develop a blood test for individuals exposed to ionizing radiation (IR) to provide a personal molecular signature of exposure and exposure-related organ damage, for guidance of treatment options, and potentially for feedback of efficacy of treatment. We will perform hypothesis-driven targeted proteomics experiments that focus upon NRF2-mediated responses to IR in mice. The experiments will address a range of mouse strains, of varying age and sex, and will investigate targeted organ IR exposure. NRF2-mediated response proteins were chosen because we previously showed that single doses of ionizing radiation from 2 to 8 Gy activated antioxidant response element (ARE)-dependent transcription (via NRF2) in breast cancer cells in a dose-dependent manner, but only after delays of a day or more. Late onset and long- lived responses are especially useful for the intended biomarker rational. Our initial experiments will focus on organs and enriched sub-fractions of blood from IR-exposed mice, to provide a panel of potential tissue- specific biomarkers, for subsequent investigation of their specific presence in blood plasma. Thus our experiments will address three general hypotheses; that there are a number of NRF2-modulated proteins that will change in tissues in a dose-dependent manner in response to IR; that the patterns of damage will provide molecular signatures that report severity of overall radiation exposure, and specific individual organ stress/damage; and that some of these potential biomarkers will leak into the blood stream and persist so that they can be measured in plasma, toward human blood tests. While our experiments focus upon IR dose- dependent responses, we note that by targeting stress proteins specific to individual organs we may find biomarkers that report individual health/distress, regardless of dose, thereby accommodating individuals with unusual sensitivity. PUBLIC HEALTH RELEVANCE: The overall rational of this proposal is the development of a blood test for individuals exposed to ionizing radiation (IR) to provide a personal molecular signature of exposure and exposure-related organ damage, for guidance of treatment options, and potentially for feedback of efficacy of treatment. The proposed work focuses upon proteins involved in delayed anti-oxidant responses to IR in different organs from IR-exposed mice, and will test for the presence of these proteins in blood. The experiments will address a range of mouse strains, of varying age and sex, and will investigate targeted organ IR exposure.