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

项目摘要 辐射暴露和辐射伤害仍然是一个真正和持续的威胁，不仅对我们的武装部队人员和 女性，而且对我们的公共健康也是如此。其中最多的是造血干细胞(HSCs)和造血。 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 在辐射损伤之后。目前，几乎没有--如果有的话--可以用来拯救致命剂量的药剂。 照射后24小时给药，可促进全系造血细胞恢复。 这一差距的持续存在对我们护理受到辐射的患者来说是一个重要的问题。 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 在照射后24小时给予硫氧还蛋白有显著的存活优势。长期目标 就是将硫氧还蛋白发展成一种治疗辐射相关的造血损伤的“可释放”制剂。这个 本应用的总体目标是确定硫氧还蛋白通过的分子机制 调节HSC功能，保护HSC免受辐射损伤。此外，作为临床应用的前奏 硫氧还蛋白的给药方案将得到优化，硫氧还蛋白的保护作用将 在非人类灵长类动物身上确定的。中心假设是硫氧还蛋白可以减轻辐射损伤。 通过改善长期再生的造血干细胞的存活率和扩张性。这些假设一直是 根据申请人实验室提供的初步数据制定的。建议的理由是 研究表明，一旦知道硫氧还蛋白如何保护HSCs免受辐射损伤，以及硫氧还蛋白的有效性 硫氧还蛋白在老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，为治疗与辐射相关的损伤患者提供了一种新的创新方法。 在强大的初步数据的指导下，这一假设将通过追求两个具体目标来检验：目标1是定义 硫氧还蛋白调节HSC功能和保护HSC抗辐射的分子机制 受伤。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。这个 硫氧还蛋白在胚胎造血中的作用将通过单一的活体成像技术来确定 单元格分辨率。目的2优化硫氧还蛋白给药方案，确定硫氧还蛋白对小鼠的保护作用 硫氧还蛋白对人源化小鼠和非人灵长类动物的影响。此外，这两个因素的组合效应 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 下定决心。申请人认为，这种方法是创新的，因为它关注的是一种新的蛋白质 在辐射暴露24小时后给予，可有效减轻辐射的毒性影响。几个 基因工程小鼠模型将被培育出来。这项拟议的研究意义重大，因为它 预计将把治疗辐射损伤的“可交付成果”制剂带到国家储备中。新的 因此，治疗辐射损伤的药物有望成为可能。

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.