4:LYMPHOMA SUPPRESSION:DNA BREAK REPAIR IN STEM CELLS AND THEIR MICROENVIRONMENT

4：淋巴瘤抑制：干细胞及其微环境中的 DNA 断裂修复

• 批准号: 7960396
• 负责人: KEVIN D MILLS
• 金额: $ 24.4万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960396
• 关键词: B-Lymphocytes; Blood Circulation; Bone Marrow; Cell physiology; Cells; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; DNA Double Strand Break; Defect; Double Strand Break Repair; Etiology; Funding; Genomic Instability; Grant; Hematopoietic; Homeostasis; Homing; Institution; Lymphocyte; Lymphoid; Lymphoid Tissue; Lymphoma; Measures; Molecular; Mus; Oncogenic; Pathway interactions; Phenotype; Population; Protein p53; Regenerative Medicine; Reporting; Research; Research Personnel; Resources; Role; Shapes; Source; Stem cells; Testing; Time; United States National Institutes of Health; cell type; fitness; leukemogenesis; neoplastic cell; repaired; stem; stem cell biology; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this project are to evaluate the roles of DNA double strand break repair in normal hematopoietic cells and microenvironments, and to assess whether specific cell types in the bone marrow niche relate to tumorigenesis. Nonhomologous end joining (NHEJ), a critical DSB repair pathway, is an important suppressor of oncogenic genome instability in developing lymphocytes. New reports now also point to a role for DSB repair in maintaining stem cell function over time, and we have recently shown that NHEJ is an important suppressor of tumorigenesis in non-lymphoid tissues. Using mice deficient for the NHEJ factor ARTEMIS and for the tumor suppressor p53, we will test our hypotheses: 1) that the NHEJ pathway is critical for the fitness and function of normal hematopoietic cells, and 2) that bone marrow and lymphoid microenvironments are key determinants of pre-B cell leukemogenesis and lymphomagenesis. Aim 1. To evaluate the extent to which NHEJ is required for normal function or homeostasis of cells in the hematopoietic compartment, we will: 1.1. measure HSC-derived cell populations in bone marrow and in circulation, and test whether NHEJ-deficient HSCs show defects in differentiation or fitness 1.2. assess genome instability in NHEJ-deficient stem and progenitor cell populations Aim 2. To determine whether specific stem cell or lymphoid microenvironments participate in shaping lymphoma phenotype, we will: 2.1. determine whether tumor latency, homing potential, or molecular etiology is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments 2.2. test whether tumor cells become adapted to specific secondary lymphoid microenvironments

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的目标是评估 DNA 双链断裂修复在正常造血细胞和微环境中的作用，并评估骨髓生态位中的特定细胞类型是否与肿瘤发生相关。 非同源末端连接 (NHEJ) 是一种关键的 DSB 修复途径，是发育中淋巴细胞中致癌基因组不稳定性的重要抑制因子。现在的新报告还指出 DSB 修复在长期维持干细胞功能中的作用，并且我们最近表明 NHEJ 是非淋巴组织肿瘤发生的重要抑制因子。 使用缺乏 NHEJ 因子 ARTEMIS 和肿瘤抑制因子 p53 的小鼠，我们将测试我们的假设：1) NHEJ 通路对于正常造血细胞的健康和功能至关重要，2) 骨髓和淋巴微环境是前 B 细胞白血病发生和淋巴瘤发生的关键决定因素。 目标 1. 为了评估造血室中细胞的正常功能或稳态需要 NHEJ 的程度，我们将： 1.1.测量骨髓和循环中的 HSC 衍生细胞群，并测试 NHEJ 缺陷的 HSC 是否表现出分化或适应性缺陷 1.2.评估 NHEJ 缺陷干细胞和祖细胞群的基因组不稳定性 目标 2. 为了确定特定的干细胞或淋巴微环境是否参与塑造淋巴瘤表型，我们将： 2.1. 确定肿瘤潜伏期、归巢潜力或分子病因学是否受到淋巴功能健全和淋巴功能缺陷的骨髓微环境的不同影响 2.2. 测试肿瘤细胞是否适应特定的次级淋巴微环境