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被辐射破坏，导致危及生命的感染，贫血， 还在流血虽然“造血综合征”的特点很好，但对长期的了解要少得多。 亚致死辐射对骨髓的影响。我们的初步研究表明， 亚致死量辐射导致迟发性血细胞减少和造血干细胞（HSC）显著减少 数字和功能。这些初步发现支持了亚致死外部辐射 导致严重的晚期骨髓损伤，特别是对HSC隔室。生物恐怖袭击或核袭击 灾难不仅会导致严重的外部辐射照射，而且还会导致内部照射， 吸入和/或摄入放射性微粒。与目前的U19研究人员合作，我们 已经确定，低剂量的内部137 Cs，不像外部辐射，导致意外严重的晚期 对造血祖细胞的影响。我们假设内部辐射可能会导致一个明显的，以前 造血系统损伤的未知模式我们还假设，外部加上内部 辐射可引起协同造血损伤并导致骨髓衰竭。在目标1和2中，我们将 更全面地定义外部与内部以及外部/内部亚致死组合的晚期效应 对干细胞、祖细胞和外周血细胞隔室的照射。更好地理解 造血系统对辐射的反应将提供一个合理的方法来减轻其影响 核事故或核袭击后。P物质类似物Homspera已被证明可以增加 造血祖细胞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，以减轻辐射引起的损伤的后期影响， 造血系统在个体发育过程中，造血部位从卵黄囊到胎肝， 出生后的骨髓在目标4中，我们将检验造血系统高度依赖于血液的假设。 在出生后早期，由于它从肝脏迁移到骨髓，因此容易受到辐射损伤。

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.