Bone Marrow - Mitigation of Bone Marrow Radiation Injury

项目4的目标是开发治疗方法，以减轻辐射对造血系统的后期影响 系统。这种强大的细胞系统会受到辐射的破坏，导致危及生命的感染、贫血、 还在流血。虽然“造血症候群”有很好的特点，但长期来看却知之甚少。 亚致死剂量辐射对骨髓的影响。我们的初步研究表明，外部 亚致死剂量辐射导致晚期细胞减少和造血干细胞(HSC)显著减少 数字和函数。这些初步发现支持以下假设：亚致死的外部辐射 导致严重的晚期骨髓损伤，特别是对HSC间室。生物恐怖袭击或核袭击 灾难不仅会导致急性外部辐射暴露，还会通过以下途径导致内部暴露 吸入和/或摄入放射性微粒。与目前的U19调查人员合作，我们 已经确定，与外部辐射不同，低剂量的内部137Cs会导致意外严重的迟发 对造血祖细胞的影响。我们假设内辐射可能会导致明显的，先前 未知的造血损伤模式。我们还假设外部加上内部 辐射可引起协同的造血损伤，并导致骨髓衰竭。在目标1和目标2中，我们将 更全面地定义外部、内部和外部/内部亚致死相结合的晚期影响 对干细胞室、祖细胞室和外周血细胞室的照射。更好地理解 造血系统对辐射的反应将为缓解辐射提供一种合理的方法。 在核事故或攻击之后。P物质类似物，Hompera，已被证明增加 造血祖细胞的数量和保护小鼠免受致命辐射。在目标3中，我们将测试 HOMSPERA，以及抗氧化剂EUK-207，以减轻辐射诱导的损伤对 造血系统。在个体发育过程中，从卵黄囊到胎肝再到 出生后的骨髓。在目标4中，我们将检验这一假设，即造血系统是高度 在出生后早期，当它从肝脏迁移到骨髓时，容易受到辐射损伤。

The targeted aim of Project 4 is to develop therapies to mitigate late effects of radiation on the hematopoietic system. This robust cellular system is damaged by radiation resulting in life-threatening infections, anemia, and bleeding. While the "hematopoietic syndrome" is well characterized, much less is known about the longterm effects of sublethal radiation on the bone marrow. Our preliminary studies indicate that external sublethal radiation leads to late cytopenias and striking decreases in hematopoietic stem cells (HSC) numbers and function. These preliminary findings support the hypothesis that sublethal external radiation causes significant late marrow injury particularly to the HSC compartment. A bioterrorist attack or nuclear disaster would lead not only to acute external radiation exposure, but also to internal exposure through inhalation and/or ingestion of radioactive particulates. In collaboration with current U19 investigators, we have determined that low dose internal 137Cs, unlike external radiation, causes unexpectedly severe late effects to hematopoietic progenitors. We hypothesize that internal radiation may cause a distinct, previously unexplored pattern of hematopoietic injury. We also hypothesize that combined external plus internal radiation may cause synergistic hematopoietic damage and lead to marrow failure. In Aims 1 and 2, we will more fully define the late effects of external versus internal versus combined external/internal sublethal irradiation on the stem, progenitor, and peripheral blood cell compartments. A better understanding of the response of the hematopoietic system to irradiation will provide for a rational approach to its mitigation following nuclear accident or attack. The substance P analog, Homspera, has been shown to increase hematopoietic progenitor numbers and protect mice from lethal radiation. In Aim 3, we will test the ability of Homspera, as well as the antioxidant EUK-207, to mitigate the late effects of radiation-induced injury to the hematopoietic system. During ontogeny, the sites of hematopoiesis transition from yolk sac to fetal liver to postnatal bone marrow. In Aim 4, we will test the hypothesis that the hematopoietic system is highly vulnerable to radiation injury as it migrates from liver to marrow in the early post-natal period.