Hematopoietic targets of radiation: identification and mitigation

摘要 造血系统对辐射损伤非常敏感，然而， 造血祖细胞和前体中间体的特异性放射敏感性 骨髓的复杂环境。这一建议的重点是理解，从而更好地 减轻辐射对红细胞和巨核细胞谱系的影响， 来自共同的双能祖细胞，共享几种细胞因子生长因子，但具有不同的 细胞生态位和独特的前体成熟过程。我们假设他们的 生物学差异导致不同的辐射敏感性，它们的共同特征提供了 共同缓解的机会。在目标1中，我们将确定不同的放射敏感性 红细胞和巨核细胞的祖细胞和前体细胞。已知几种细胞因子 保护红细胞和巨核细胞前体细胞免于细胞死亡。在目标2中，我们定义 单一和联合细胞因子治疗减轻放射损伤能力及探索 是否这两个谱系从一个共同的祖先出现导致细胞因子 治疗有利于减轻一个血统的损害其他。在目标3中，我们 研究辐射对红细胞和巨核细胞前体的不同小生境的损伤， 从而为未来缓解造血前体的新方法奠定基础 通过保护他们的细胞龛。生物恐怖袭击或重大核灾难不会导致 急性外照射，但也可能涉及二次内照射 通过吸入和摄入放射性微粒，正如在一些 核事故。在目标4中，我们将利用内暴露的小鼠模型 最近在罗切斯特大学建立，开始描绘慢性， 低剂量的骨髓内照射更好地了解 造血系统及其微环境对辐射暴露的影响将提供合理的 在发生核事故或核攻击时采取缓解核威胁的方法，从而加强 造血恢复和提高原发性受害者及其救助者存活率。公共卫生声明：拟议的研究旨在了解 骨髓中的血细胞对辐射很敏感， 这些细胞。

Abstract The hematopoietic system is exquisitely sensitive to radiation injury, however, little is known of the specific radiosensitivity of hematopoietic progenitor and precursors intermediates in the complex milieu of the marrow. This proposal is focused on understanding, and thus better mitigating, the effects of radiation on the erythroid and megakaryocyte lineages that originate from a common bipotential progenitor, share several cytokine growth factors, but have distinct cellular niches and unique processes of precursor maturation. We hypothesize that their biological differences lead to differential radiation sensitivity and their shared features provide opportunities for common mitigation. In Aim 1, we will determine the differential radiosensitivity of erythroid and megakaryocyte progenitors and precursors. Several cytokines are known to protect both erythroid and megakaryocyte precursors from cell death. In Aim 2, we will define the ability of single and combination cytokine therapy to mitigate radiation injury and explore whether the emergence of these two lineages from a common progenitor causes cytokine therapy to favor the mitigation of one lineage to the detriment of the other. In Aim 3, we will investigate radiation damage to the distinct niches of erythroid and megakaryocyte precursors, and thus lay the groundwork for future novel approaches of mitigating hematopoietic precursors by protecting their cellular niches. A bioterrorist attack or major nuclear disaster would lead not only to acute external radiation exposure, but may also involve secondary internal exposure through inhalation and ingestion of radioactive particulates, as has been seen in a number of nuclear incidents. In Aim 4, we will take advantage of a murine model of internal exposure recently established at the University of Rochester to begin to delineate the effects of chronic, low dose, internal radiation on the bone marrow. A better understanding of the response of the hematopoietic system and its microenvironment to radiation exposure will provide for a rational approach to its mitigation in the face of a nuclear accident or attack and, thus, enhance hematopoietic recovery and improve survival of primary victims as well their rescuers. PUBLIC HEALTH STATEMENT: The proposed research is designed to learn which blood cells in the bone marrow are sensitive to radiation and to learn how to protect these cells.