GATA-2 MEDIATED REGULATION OF NORMAL AND LEUKEMIC STEM/PROGENITOR CELL FUNCTION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 GATA-2是锌指GATA转录因子家族的第二个成员，在造血和其他组织系统中影响细胞的命运。GATA-2-/-在E10-11患有严重贫血时是胚胎致死的；排除了对成人造血室的分析。GATA-2+/-小鼠在成年期存活，为探索成人造血提供了一种顺从的模型。 事实上，罗德里格斯博士将专注于“GATA-2介导的正常和白血病干细胞/祖细胞功能的调节”。研究这种转录因子并确定其作用，不仅对肿瘤，而且对干细胞的转录调控和组织修复都有重要的影响。该项目使用白血病过程作为干细胞转录调控的模型。总体而言，提出的假设是GATA-2是一种支持髓系白血病干细胞的转录因子。为了解决这一假设，将解决以下具体目标： 1)在小鼠急性髓系白血病(AML)的白血病干细胞(LSC)隔室中敲除GATA-2，并评估其对LSC功能和体内白血病进展的影响。 2)评估GATA-2的降低对体外培养的LSC功能的影响，如细胞周期、细胞凋亡等。 3)评估GATA-2的减少如何影响LSC基因表达谱(GATA-2 LSC靶基因)，具体地说，将其与正常HSC/祖细胞中的GATA-2基因靶向程序进行比较 最终，在研究干细胞分化转录调控的总体范围内，该项目将确定可以在LSCs/白血病中特异性靶向的GATA-2下游介质。从这些研究中收集的信息也可能为在其他环境中调节恶性肿瘤提供洞察力，包括组织损伤和修复。

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. GATA-2 is the second member of the zinc finger GATA family of transcription factors which influence cell fate in hematopoietic and other tissue systems. GATA-2 -/- are embryonic lethal at e10-11 with severe anemia; precludes analysis of adult hematopoietic compartment. GATA-2 +/- mice survive throughout adulthood and provide an amenable model to probe adult hematopoiesis. Indeed, Dr. Rodrigues will focus on "GATA-2 mediated regulation of normal and leukemic stem/progenitor cell function". Studying this transcription factor and determining its role has important repercussions not only for neoplasia, but for the transcriptional regulation of stem cells and tissue repair. The project uses the leukemic process as a model for transcriptional regulation of stem cells. Overall, the proposed hypothesis is that GATA-2 is a transcription factor that sustains myeloid leukemic stem cells. To address this hypothesis, the following specific aims will be addressed: 1) Knockdown GATA-2 in leukemic stem cell (LSC) compartment of mouse AML and evaluate how this impacts LSC function and leukemia progression in vivo. 2) Assess how reduction of GATA-2 impacts cellular LSC function in vitro e.g. cell cycle, apoptosis. 3) Evaluate how reduction of GATA-2 affects the LSC gene expression profile (GATA-2 LSC target genes) and, specifically, compare this to GATA-2 gene target program in normal HSCs/progenitors Ultimately, within the overall scope of studying transcriptional regulation of stem cell differentiation, the project will identify downstream mediators of GATA-2 that can be specifically targeted in LSCs/leukemia. The information gleaned from these studies may also afford insights into regulation of malignancy in other settings, including tissue injury and repair.