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

项目总结

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.