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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 DNA链断裂的受控诱导对于许多细胞和发育过程至关重要，但也带来了基因组不稳定和随之而来的疾病的风险。 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）越来越被认为是防止发育中淋巴细胞致癌染色体不稳定性的关键因素。 除此之外，DSBR在维持正常干细胞功能和适应性方面的作用已经被提出。 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，有或没有肿瘤抑制因子p53，我们将通过1）测量正常造血干细胞、祖细胞和子代细胞的适应性和功能;和2）评估DSBR活性或缺陷骨髓和淋巴微环境中的致瘤性来检验这一假设。 目标1。为了评估造血区室中细胞的正常功能或稳态需要NHEJ的程度，我们将：（1）测量骨髓和循环中的HSC衍生的细胞群，并测试NHEJ缺陷的HSC或其邻近后代的分化或功能是否受损，以及（2）评估NHEJ缺陷的干细胞和祖细胞群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）确定肿瘤潜伏期、归巢潜力或分子病因是否受到淋巴活性与淋巴缺陷骨髓微环境的不同影响;（2）检测肿瘤细胞是否适应特定的次级淋巴微环境

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