Hematopoietic targets of radiation: identification and mitigation

描述（由申请人提供）：造血系统对辐射损伤非常敏感，然而，在复杂的骨髓环境中，对造血祖细胞和前体中间体的特异性放射敏感性知之甚少。这一建议的重点是了解，从而更好地减轻辐射对红系和巨核细胞谱系的影响，它们起源于共同的双电位祖细胞，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Aim 1中，我们将确定红细胞和巨核细胞祖细胞和前体的放射敏感性差异。已知有几种细胞因子可保护红细胞和巨核细胞前体免于细胞死亡。在Aim 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，并探讨这两种谱系来自共同祖先的出现是否导致细胞因子治疗有利于减轻一种谱系而损害另一种谱系。在Aim 3中，我们将研究辐射对红细胞和巨核细胞前体不同生态位的损伤，从而为未来通过保护细胞生态位来减轻造血前体的新方法奠定基础。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，而且还可能涉及通过吸入和摄入放射性微粒而发生的二次内部辐射暴露，这在若干核事件中已经看到。在Aim 4中，我们将利用最近在罗切斯特大学建立的小鼠内照射模型，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的缓解提供合理的方法，从而增强造血恢复，提高主要受害者及其救援者的生存率。公共卫生声明：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.