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: 8167690
• 负责人: KEVIN D MILLS
• 金额: $ 25.04万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167690
• 关键词: Blood Circulation; Bone Marrow; Cell physiology; Cells; Chromosomal Instability; Computer Retrieval of Information on Scientific Projects Database; DNA Double Strand Break; DNA strand break; Development; Developmental Process; Disease; Double Strand Break Repair; Etiology; Funding; Genomic Instability; Grant; Hematopoietic; Hematopoietic System; Homeostasis; Homing; Institution; Lymphocyte; Lymphoid; Lymphoma; Malignant Neoplasms; Measures; Molecular; Mus; Neoplastic Cell Transformation; Nonhomologous DNA End Joining; Oncogenic; Phenotype; Population; Protein p53; Research; Research Personnel; Resources; Risk; Role; Shapes; Source; Stem cells; Testing; Time; Tumorigenicity; United States National Institutes of Health; cell type; fitness; neoplastic cell; prevent; progenitor; repaired; stem; tumor

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 controlled induction of DNA strand breaks is critical for many cellular and developmental processes, but also poses the risk of genomic instability and consequent disease. The objectives of this project are to understand the roles of DNA double strand break repair in normal development within the hematopoietic system, and to assess whether specific cell types in the bone marrow hematopoietic niche may relate to cancer. DNA double strand break repair (DSBR) is increasingly recognized as a critical factor in preventing oncogenic chromosome instability in developing lymphocytes. Beyond this, roles have been suggested for DSBR in maintaining normal stem cell function and fitness over time. I hypothesize that DSBR is critical in both hematopoietic cells and their surrounding microenvironments to promote normal development and prevent neoplastic transformation. Using mice deficient for DSBR, with or without the tumor suppressor p53, we will test this hypothesis by 1) measuring the fitness and function of normal hematopoietic stem, progenitor, and progeny cells; and 2) evaluating tumorigenicity in DSBR competent or defective bone marrow and lymphoid microenvironments. 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) measure HSC-derived cell populations in bone marrow and in the circulation, and test whether NHEJ-deficient HSCs or their proximate descendants are impaired for differentiation or function and (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 the lymphoma phenotype, we will: (1) determine whether tumor latency, homing potential, or molecular etiology is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments; and (2) test whether tumor cells become adapted to specific secondary lymphoid microenvironments

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 DNA链断裂的可控诱导对于许多细胞和发育过程是至关重要的，但也带来了基因组不稳定和随后的疾病的风险。该项目的目的是了解DNA双链断裂修复在造血系统正常发育中的作用，并评估骨髓造血生态位中的特定细胞类型是否与癌症有关。DNA双链断裂修复(DSBR)被越来越多地认为是在发育中的淋巴细胞中防止致癌染色体不稳定性的关键因素。除此之外，随着时间的推移，DSBR在维持正常干细胞功能和健康方面的作用也被提出。我推测DSBR在造血细胞及其周围的微环境中对于促进正常发育和防止肿瘤转化都是至关重要的。使用缺乏DSBR的小鼠，无论是否有肿瘤抑制基因P53，我们将通过1)测量正常造血干细胞、祖细胞和后代细胞的适合性和功能；以及2)评估DSBR合格或缺陷的骨髓和淋巴微环境中的致瘤性来验证这一假说。 目的1.为了评估NHEJ在多大程度上需要造血室细胞的正常功能或稳态，我们将：(1)测量骨髓和循环中的HSC来源的细胞群，并测试NHEJ缺陷的HSC或其近缘后代是否在分化或功能上受到损害；(2)评估NHEJ缺陷的干细胞和祖细胞群体的基因组不稳定性 目的2.为了确定特定的干细胞或淋巴微环境是否参与了淋巴瘤表型的形成，我们将：(1)确定肿瘤潜伏期、归巢潜能或分子病因学是否受到淋巴功能和淋巴缺乏的骨髓微环境的不同影响；以及(2)测试肿瘤细胞是否适应特定的次级淋巴微环境