Molecular modulators of radiation-induced chromosome instability and hematopoietic damage

摘要 造血系统是最易受短时辐射影响的器官系统之一。 以及长期的损害。有效地从病理或药物诱导的骨髓中恢复 失败是由造血干细胞和骨髓固有的敏感性决定的。 环境利基。识别影响造血恢复的分子对于 针对辐射损伤的新型医学对策的发展。我们的预赛 研究表明，即使只有一个Bccip拷贝的丢失，也会使小鼠对 辐射诱导的造血综合征和淋巴肿大，以及BCCIP的招募 对DNA的损伤部位取决于PARP1。我们假设Bccip单倍体不足 可使造血干细胞对辐射杀伤敏感，损害长期生存能力 干细胞重建造血系统，和/或影响骨髓生态位的能力 滋养造血。在目标1中，将使用一系列长期和短期实验 为了确定Bccip单倍体不足是否增强了对造血干细胞的杀伤和 祖细胞，削弱干细胞重建骨髓的能力，并降低 骨髓生态位对造血的滋养作用。我们还假设Bccip 单倍体功能不全改变骨髓祖细胞对肿瘤起始和转移的敏感性 随后的肿瘤进展。在目标2中，我们将通过检查肿瘤来检验这一假设 肿瘤的克隆性和染色体重排景观的确定 利用新开发的基因组和计算技术建立野生型和Bccip半缺陷小鼠 接近了。在目标3中，我们将确定BCCIP的PARYLAITON依赖机制 被招募并保留在DNA损伤部位。这些研究的完成将阐明 Bccip在辐射损伤后的造血调控和抑制中的独特作用 辐射诱导的肿瘤发生。

Abstract The hematopoietic system is one of the organ systems most vulnerable to radiation induced short- and long- term damage. Efficient recovery from pathological or medically induced bone marrow failure is dictated by the intrinsic sensitivity of the hematopoietic stem cell and the bone marrow environment niche. Identification of molecules that affect hematopoietic recovery is essential to the development of novel medical countermeasures against radiation damage. Our preliminary studies suggested that loss of even a single copy of Bccip confers hypersensitivity of mice to radiation-induced hematopoietic syndrome and lymphomagenesis, and the recruitment of BCCIP to DNA damage sites are dependent on PARP1. We hypothesize that Bccip haploinsufficiency can sensitize the hematopoietic stem cells to radiation killing, impair the long-term competency of stem cell to reconstitute the hematopoietic system, and/or affect the bone marrow niche’s capacity to nourish hematopoiesis. In Aim 1, a series of long-term and short-term experiments will be used to determine whether Bccip haploinsufficiency enhances the killing of hematopoietic stem and progenitor cells, impair stem cells’ capacity to reconstitute the bone marrow, and diminish the ability of bone marrow niche to nourish the hematopoiesis. We also hypothesize that Bccip haploinsufficiency alters the bone marrow progenitor cell susceptibility to tumor initiation and subsequent tumor progression. In Aim 2, we will test this hypothesis by examining the tumor clonality and defining the landscapes of chromosome rearrangements in the tumors formed in wild type and Bccip haplo-insufficient mice using newly developed genomic and computational approaches. In Aim 3, we will determine the PARylaiton dependent mechanism by which BCCIP is recruited and retained at the DNA damage sites. Completion of these studies will elucidate a unique role of Bccip in modulating hematopoiesis after radiation damage and in suppressing radiation-induced tumorigenesis.