Hematopoietic targets of radiation: identification and mitigation

描述(申请人提供)：造血系统对辐射损伤非常敏感，然而，对骨髓复杂环境中造血祖细胞和前体中间体的特定辐射敏感性知之甚少。这一建议的重点是了解辐射对红系和巨核细胞系的影响，从而更好地减轻辐射对红系和巨核系的影响，这些红系和巨核系起源于共同的双潜能祖细胞，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，它们的生物学差异导致了不同的辐射敏感性，它们的共同特征为共同缓解提供了机会。在目标1中，我们将确定红系和巨核系祖细胞和前体细胞的不同辐射敏感性。已知有几种细胞因子可以保护红系和巨核系前体细胞免于细胞死亡。在目标2中，我们将定义单一和联合细胞因子治疗减轻辐射损伤的能力，并探索这两个谱系的出现是否会导致细胞因子治疗有利于一个谱系的缓解而损害另一个谱系。在目标3中，我们将研究辐射对红系和巨核细胞前体细胞壁龛的损伤，从而为未来通过保护其细胞壁龛来减轻造血祖细胞壁龛的新方法奠定基础。生物恐怖袭击或重大核灾难不仅会导致急性外部辐射暴露，还可能涉及通过吸入和摄取放射性微粒进行二次内部暴露，正如在一些核事件中所看到的那样。在目标4中，我们将利用罗切斯特大学最近建立的内照射小鼠模型，开始描述慢性、低剂量内照射对骨髓的影响。更好地了解造血系统及其微环境对辐射暴露的反应，将为面对核事故或核攻击时减轻辐射的影响提供合理的方法，从而促进造血恢复，改善初级受害者及其救助者的存活率。公共卫生声明：这项拟议的研究旨在了解骨髓中哪些血细胞对辐射敏感，并了解如何保护这些细胞。

DESCRIPTION (provided by applicant): 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.