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

描述（由申请方提供）：本提案的总体合理性是为暴露于电离辐射（IR）的个体开发一种血液检测，以提供暴露和辐射相关器官损伤的个人分子特征，用于指导治疗选择，并可能用于治疗疗效的反馈。我们将进行假设驱动的靶向蛋白质组学实验，重点是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，并将研究靶器官的IR暴露。选择NRF 2介导的反应蛋白是因为我们以前表明，2至8戈伊的单剂量电离辐射以剂量依赖性方式激活乳腺癌细胞中的抗氧化反应元件（ARE）依赖性转录（通过NRF 2），但仅在延迟一天或更长时间后。迟发性和长期缓解对于预期生物标志物合理性特别有用。我们的初始实验将集中于来自IR暴露小鼠的器官和血液的富集亚组分，以提供一组潜在的组织特异性生物标志物，用于随后研究其在血浆中的特异性存在。因此，我们的实验将解决三个一般性假设：有一些NRF2调节的蛋白质将在组织中以剂量依赖性方式响应IR而改变;损伤模式将提供分子特征，其报告总体辐射暴露的严重性和特定的个体器官应激/损伤;并且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测量，用于人类血液测试。虽然我们的实验集中于IR剂量依赖性反应，但我们注意到，通过靶向对个体器官特异性的应激蛋白，我们可以发现报告个体健康/痛苦的生物标志物，而不管剂量如何，从而适应具有异常敏感性的个体。 公共卫生相关性：该提案的总体合理性是为暴露于电离辐射（IR）的个人开发血液检测，以提供暴露和辐射相关器官损伤的个人分子特征，用于指导治疗方案，并可能用于治疗效果的反馈。拟议的工作集中在蛋白质参与延迟抗氧化反应IR在不同的器官从IR暴露的小鼠，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，并将研究靶器官的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.