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

GATA-2 介导的正常和白血病干细胞/祖细胞功能的调节

• 批准号: 8360044
• 负责人: Neesha Rodrigues
• 金额: $ 2.55万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360044
• 关键词: Address; Adult; Affect; Anemia; Apoptosis; Cell Cycle; Cell physiology; Cells; Embryo; Family; Funding; Gene Expression Profile; Gene Targeting; Glean; Grant; Hematopoiesis; Hematopoietic; In Vitro; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mus; Myelogenous; National Center for Research Resources; Neoplasms; Principal Investigator; Process; Regulation; Research; Research Infrastructure; Resources; Role; Source; Stem cells; System; Tissues; Transcriptional Regulation; United States National Institutes of Health; Wound Healing; Zinc Fingers; cost; in vivo; injury and repair; insight; leukemia; member; novel strategies; progenitor; programs; stem; stem cell differentiation; transcription factor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 GATA-2是锌指GATA转录因子家族的第二个成员，该家族会影响造血和其他组织系统中细胞命运。 GATA-2 - / - 在E10-11处具有严重贫血的E10-11胚胎致死；排除成人造血室的分析。 GATA-2 +/-小鼠在整个成年期生存，并为探测成人造血的模型提供了可正常的模型。 实际上，罗德里格斯博士将重点介绍“ GATA-2介导的正常和祖细胞/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症，而且对干细胞和组织修复的转录调节产生了重要影响。该项目使用白血病过程作为干细胞转录调节的模型。总体而言，提出的假设是GATA-2是持续髓样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）小鼠AML的白血病干细胞（LSC）中敲低gata-2，并评估这如何影响体内LSC功能和白血病进展。 2）评估GATA-2的还原如何影响细胞LSC在体外的功能，例如细胞周期，凋亡。 3）评估GATA-2的还原如何影响LSC基因表达谱（GATA-2 LSC靶基因），并具体将其与正常HSC/祖细胞中的GATA-2基因靶程序进行比较 最终，在研究干细胞分化的转录调控的总体范围内，该项目将确定可以在LSC/白血病中专门针对的GATA-2的下游介质。从这些研究中收集的信息也可能可以洞悉其他环境中恶性肿瘤的调节，包括组织损伤和修复。