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: 8360266
• 负责人: KEVIN D MILLS
• 金额: $ 15.09万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360266
• 关键词: Bone Marrow; Cell physiology; Cells; Centers of Research Excellence; DNA; DNA Double Strand Break; Defect; Development; Developmental Process; Double Strand Break Repair; Funding; Genomic Instability; Grant; Hematopoietic; Homeostasis; Lymphoid; Lymphoma; Malignant Neoplasms; Measures; Mus; National Center for Research Resources; Neoplastic Cell Transformation; Nonhomologous DNA End Joining; Phenotype; Population; Principal Investigator; Protein p53; Regenerative Medicine; Research; Research Infrastructure; Resources; Role; Shapes; Source; Stem cells; Testing; Tumor Suppression; Tumorigenicity; United States National Institutes of Health; cell type; cost; fitness; lymphoid neoplasm; neoplastic cell; prevent; progenitor; repaired; stem; stem cell biology; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. DNA breaks are critical for many cellular and developmental processes, but must be correctly repaired to prevent genome instability. The objectives of this project are to understand the roles of DNA double strand break repair (DSBR) in normal hematopoietic development, and to determine whether DSBR defects in specific cell types in the bone marrow may relate to cancer development. DSBR is known to be a key factor in lymphoid tumor suppression, but has been less well characterized in other cell types. 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 measuring the fitness and function of normal hematopoietic stem, progenitor, and progeny cells; and by 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) test whether DSBR-deficient HSCs or their descendants are impaired for differentiation or function and (2) measure genome instability in DSBR-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 tumorigenesis 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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 DNA断裂对许多细胞和发育过程至关重要，但必须正确修复以防止基因组不稳定。 该项目的目的是了解DNA双链断裂修复（DSBR）在正常造血发育中的作用，并确定骨髓中特定细胞类型的DSBR缺陷是否与癌症发展有关。 已知DSBR是淋巴肿瘤抑制的关键因素，但在其他细胞类型中的特征不太清楚。 我假设DSBR在造血细胞及其周围微环境中促进正常发育和防止肿瘤转化是至关重要的。 使用DSBR缺陷的小鼠，有或没有肿瘤抑制基因p53，我们将测试这一假设，通过测量正常造血干细胞，祖细胞和后代细胞的适应性和功能，并通过评估在DSBR主管或有缺陷的骨髓和淋巴微环境的致瘤性。 目标1.为了评估NHEJ对于造血区室中细胞的正常功能或稳态所需的程度，我们将：（1）测试DSBR缺陷型HSC或其后代的分化或功能是否受损，以及（2）测量DSBR缺陷型干细胞和祖细胞群体中的基因组不稳定性 目标2.为了确定特定的干细胞或淋巴微环境是否参与淋巴瘤表型的形成，我们将：（1）确定肿瘤发生是否受到淋巴活性与淋巴缺陷骨髓微环境的不同影响;（2）测试肿瘤细胞是否适应特定的次级淋巴微环境