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

硫氧还蛋白，一种减轻辐射引起的造血损伤的新型药物

• 批准号: 10687418
• 负责人: Yubin Kang
• 金额: $ 44.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687418
• 关键词: Acute; Address; Antioxidants; Bone marrow failure; Cell Aging; Cell Lineage; Cell Proliferation; Cells; Clinical; DNA Double Strand Break; Data; Effectiveness; Embryo; Erythropoietin; Exposure to; Genetically Engineered Mouse; Goals; Granulocyte Colony-Stimulating Factor; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Hour; Human; Imaging Techniques; Infection; Injury; Knock-out; Knockout Mice; Knowledge; Laboratories; Low Dose Radiation; Mediating; Mission; Molecular; Mus; Organ; Outcome; Oxidoreductase; Patient Care; Patient-Focused Outcomes; Patients; Play; Proteins; Proteomics; Public Health; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Protection; Radiation exposure; Radioactive; Recovery; Regimen; Regulation; Research; Resolution; Role; Safety; Services; Signal Pathway; Solid; Survival Rate; Syndrome; TP53 gene; TXN gene; Terrorism; Testing; Therapeutic; Therapeutic Agents; Thrombopoietin; Tissues; Toxic effect; United States National Institutes of Health; Woman; Work; care outcomes; cell growth; clinical application; combinatorial; conditional knockout; dirty bomb; disability; effectiveness evaluation; humanized mouse; improved; improved functioning; innovation; intravital imaging; irradiation; men; mouse model; nonhuman primate; novel; novel therapeutics; p53 Signaling Pathway; protective effect; radiation effect; stem cell function; stem cells; translational impact

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.

项目概要 辐射暴露和辐射损伤仍然是一个真实而持续的威胁，不仅对我们的武装军人， 妇女，也关系到我们的公共健康。造血干细胞（HSC）和造血功能是最重要的 对放射损伤和造血综合征敏感的组织/器官仍然是首要的治疗挑战 放射损伤后。目前，可用于挽救致命剂量的药物（如果有的话）非常少 辐射后 24 小时给予，可减轻辐射损伤并增强全谱系造血细胞的恢复。 这种差距的持续存在对我们护理暴露于辐射的患者来说是一个重要问题。 申请人的初步研究表明硫氧还蛋白具有显着的保护和增殖作用 对 HSC 的影响以及照射后 24 小时给予硫氧还蛋白的显着生存优势。长期目标 的目标是将硫氧还蛋白开发成一种“可交付”的药物，用于治疗辐射相关的造血损伤。这 本申请的总体目标是确定硫氧还蛋白通过的分子机制 调节 HSC 功能并保护 HSC 免受辐射损伤。此外，作为临床应用的前奏 优化硫氧还蛋白给药方案，提高硫氧还蛋白的保护作用 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 通过改善长期重新增殖的 HSC 的存活和扩张。这些假设已被 根据申请人实验室产生的初步数据制定。拟议的理由 研究表明，一旦了解硫氧还蛋白如何保护 HSC 免受辐射损伤以及其有效性 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，我们将能够继续前进 临床应用，为治疗辐射相关损伤患者提供了一种新的创新方法。 在强有力的初步数据的指导下，该假设将通过追求两个具体目标进行检验：目标 1 是定义 硫氧还蛋白调节 HSC 功能并保护 HSC 免受辐射的分子机制 受伤。将研究p53信号通路在硫氧还蛋白介导的辐射防护中的作用。这 硫氧还蛋白在胚胎造血中的作用将通过活体成像技术确定 细胞分辨率。目标 2 是优化小鼠硫氧还蛋白给药方案并确定保护作用 硫氧还蛋白对人源化小鼠和非人灵长类动物的影响。此外，组合效应 硫氧还蛋白和造血细胞生长因子（G-CSF）在减轻放射损伤方面的作用 决定。申请人认为，该方法具有创新性，因为它专注于一种新型蛋白质，该蛋白质是 暴露于辐射 24 小时后，可有效减轻辐射的毒性作用。一些 将产生基因工程小鼠模型。拟议的研究意义重大，因为它 预计将把治疗辐射损伤的“成果”药剂纳入国家储备。新的 由此，放射线损伤的治疗剂有望成为可能。