Thioredoxin, a novel agent for mitigating radiation-induced hematopoietic injury

项目摘要 辐射暴露和辐射损伤仍然是一个真实的和持续的威胁，不仅对我们的武装部队人员， 妇女，也是我们的公共健康。造血干细胞（HSC）和造血是其中最重要的 对辐射损伤和造血综合征敏感的组织/器官仍然是治疗的首要挑战 辐射损伤后。目前，有很少-如果有的话-代理人可以用来挽救致命剂量 照射后24小时给药可明显减轻辐射损伤并促进全系造血细胞恢复。 这种差距的持续存在是我们护理暴露于辐射的患者的一个重要问题。 申请人的初步研究表明硫氧还蛋白具有显著的保护和增殖作用， 照射后24小时给予硫氧还蛋白具有显著的存活优势。远景目标 是将硫氧还蛋白开发成用于治疗辐射相关造血损伤的“可递送”药剂。的 本申请的总体目的是确定硫氧还蛋白 调节HSC功能并保护HSC免受辐射损伤。此外，作为临床应用的前奏， 硫氧还蛋白给药方案将被优化，硫氧还蛋白的保护作用将被 在非人类灵长类动物中测定。中心假设是硫氧还蛋白减轻辐射损伤 通过改善长期再生HSC的存活和扩增。这些假设已经 根据申请人实验室产生的初步数据制定。建议的理由 研究表明，一旦知道硫氧还蛋白如何保护HSC免受辐射损伤， 硫氧还蛋白在小鼠和非人类灵长类动物中进行了优化和测试，我们将能够向前迈进， 临床应用，为放射相关损伤患者的治疗提供了一种新的创新方法。 在强有力的初步数据的指导下，将通过追求两个具体目标来检验这一假设： 硫氧还蛋白调节HSC功能和保护HSC免受辐射的分子机制 损伤p53信号通路在硫氧还蛋白介导的辐射防护中的作用将被研究。的 硫氧还蛋白在胚胎造血中的作用将使用单次活体成像技术来确定。 细胞分辨率目的2：优化硫氧还蛋白给药方案， 硫氧还蛋白在人源化小鼠和非人灵长类动物中的作用。此外， 硫氧还蛋白和造血细胞生长因子（G-CSF）在减轻辐射损伤中的作用将是 测定在申请人看来，该方法是创新的，因为它聚焦于一种新的蛋白质， 当在辐射暴露24小时后给予时，有效减轻辐射的毒性作用。几 将产生基因工程小鼠模型。这项研究意义重大，因为它 预计将把“可交付”剂的国家储备，用于治疗辐射损伤。新 因此，预期可获得用于放射损伤的治疗剂。

Project Summary Radiation exposure and radiation injury remain a real and constant threat not only to our armed service men and women, but also to our public health. Hematopoietic stem cells (HSCs) and hematopoiesis are among the most sensitive tissues/organs to radiation injury and hematopoietic syndrome remains the first therapeutic challenge following radiation injury. Currently, there are very few - if any - agents that can be used to rescue lethal dose radiation injury and enhance all-lineage hematopoietic cell recovery when given 24 hours after irradiation. Continued existence of this gap represents an important problem to our care for patients exposed to radiation. The preliminary study by the applicant demonstrated marked protective and proliferative effects of thioredoxin on HSCs and a significant survival advantage of giving thioredoxin 24 hours after irradiation. The long-term goal is to develop thioredoxin into a “deliverable” agent for the treatment of radiation-related hematopoietic injury. The overall objective in this application are to determine the molecular mechanisms through which thioredoxin regulates HSC function and protects HSCs from radiation injury. Additionally, as a prelude to clinical application the thioredoxin administration regimen will be optimized and the protective effects of thioredoxin will be determined in non-human primates. The central hypothesis is that thioredoxin mitigates against radiation injury by improving the survival and expansion of long-term repopulating HSCs. These hypotheses have been formulated on the basis of preliminary data produced in the applicant’s laboratory. The rationale for the proposed research is that, once it is known how thioredoxin protects HSCs from radiation injury and the effectiveness of thioredoxin is optimized and tested in both mice and non-human primates, we will be able to move forward into clinical use, generating a new and innovative approach for the treatment of patients with radiation related injury. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: Aim 1 is to define the molecular mechanisms through which thioredoxin regulates HSC function and protects HSCs from radiation injury. The role of p53 signaling pathway in thioredoxin mediated radiation protection will be investigated. The role of thioredoxin in embryonic hematopoiesis will be determined using intravital imaging technique with single cell resolution. Aim 2 is to optimize thioredoxin administration regimen in mice and determine the protective effects of thioredoxin in humanized mice and in non-human primates. Additionally, the combinatorial effects of thioredoxin and hematopoietic cell growth factors (G-CSF) in mitigating against radiation injury will be determined. The approach is innovative, in the applicant’s opinion, because it focuses on a novel protein that is effective in mitigating the toxic effects of radiation when given after 24 hours of radiation exposure. Several genetically engineered mouse models will be generated. The proposed research is significant, because it is expected to bring “deliverables” agent to the national stockpile for the treatment of radiation injury. New therapeutic agents for radiation injury are expected to become attainable as a result.