Molecular modulators of radiation-induced chromosome instability and hematopoietic damage

辐射引起的染色体不稳定和造血损伤的分子调节剂

• 批准号: 10626749
• 负责人: Zhiyuan Shen
• 金额: $ 36.78万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626749
• 关键词: Acceleration; Acute; Adult; Affect; Animals; BARD1 gene; BRCA2 gene; Binding; Bone Marrow; Bone Marrow Cells; Bone marrow failure; Carcinogens; Chromosomal Breaks; Chromosomal Instability; Chromosomal Stability; Chromosomes; Clonality; Competence; DNA Damage; DNA Double Strand Break; DNA Repair; Development; Environment; Genes; Genome Stability; Genomics; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hypersensitivity; Impairment; Ionizing radiation; Longevity; Lymphoma; Lymphomagenesis; Mediating; Medical; Modeling; Molecular; Mus; Natural regeneration; Nature; Normal tissue morphology; Nucleotides; Organ; Pathologic; Poly Adenosine Diphosphate Ribose; Predisposition; Process; Proliferating; Property; Proteins; Radiation; Radiation Tolerance; Radiation exposure; Radiation induced damage; Recovery; Role; Series; Site; Syndrome; Testing; Tumor Promotion; body system; epigenomics; experimental study; genome-wide; in vivo; insight; mature animal; medical countermeasure; novel; radiation effect; reconstitution; recruit; stem; stem cells; tissue regeneration; tumor; tumor initiation; tumor progression; tumorigenesis

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.

摘要 造血系统是最容易受到辐射引起的短- 和长期损害。从病理或药物诱导的骨髓中有效恢复 失败是由造血干细胞和骨髓的内在敏感性决定的 环境生态位鉴定影响造血恢复的分子对于 针对辐射损伤的新型医疗对策的开发。我们的初步 研究表明，即使是Bccip的一个拷贝的丢失也会使小鼠对 辐射诱导的造血综合征和淋巴瘤生成，以及BCCIP的募集 DNA损伤位点依赖于PARP 1。我们假设Bccip单倍不足 可以使造血干细胞对辐射杀伤敏感，损害造血干细胞的长期能力， 干细胞重建造血系统，和/或影响骨髓小生境的能力 滋养造血系统。在目标1中，将使用一系列长期和短期实验 为了确定Bccip单倍不足是否增强造血干细胞的杀伤， 祖细胞，损害干细胞重建骨髓的能力，并减少 骨髓龛滋养造血的能力。我们还假设Bccip 单倍不足改变了骨髓祖细胞对肿瘤发生的易感性， 随后的肿瘤进展。在目标2中，我们将通过检查肿瘤来验证这一假设。 克隆性，并确定在肿瘤中形成的染色体重排的景观， 野生型和Bccip单倍体不足的小鼠，使用新开发的基因组和计算 接近。在目标3中，我们将确定BCCIP依赖于PARylaiton的机制， 在DNA损伤位点被募集和保留。这些研究的完成将阐明 Bccip在调节辐射损伤后造血和抑制辐射损伤中的独特作用 辐射诱发的肿瘤发生。

项目成果

BCCIPβ modulates the ribosomal and extraribosomal function of S7 through a direct interaction.

BCCIPβ 通过直接相互作用调节 S7 的核糖体和核糖体外功能

• DOI: 10.1093/jmcb/mjx019
• 发表时间: 2017-06-01
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5
• 作者: Ba Q;Li X;Huang C;Li J;Fu Y;Chen P;Duan J;Hao M;Zhang Y;Li J;Sun C;Ying H;Song H;Zhang R;Shen Z;Wang H
• 通讯作者: Wang H

SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.

• DOI: 10.1093/nar/gkw748
• 发表时间: 2016-10-14
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Hong X;Liu W;Song R;Shah JJ;Feng X;Tsang CK;Morgan KM;Bunting SF;Inuzuka H;Zheng XF;Shen Z;Sabaawy HE;Liu L;Pine SR
• 通讯作者: Pine SR