Role of the ultraconserved genomic regions (UCRs) in hematopoiesis
超保守基因组区域 (UCR) 在造血中的作用
基本信息
- 批准号:8119543
- 负责人:
- 金额:$ 19.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2012-07-31
- 项目状态:已结题
- 来源:
- 关键词:Binding SitesBiological AssayBiologyBloodBlood CellsBlood PlateletsBone Marrow TransplantationCD34 geneCellsCodeComplementary DNAComplexDataDevelopmentDiseaseElementsErythrocytesErythroidFamilyFunctional RNAGene ExpressionGenomeGenomicsGoalsHematopoiesisHematopoieticHematopoietic SystemHematopoietic stem cellsHumanHuman GenomeImmunophenotypingIn VitroMalignant NeoplasmsMegakaryocytesMicroRNAsMolecularMorphologyNamesOncogenesPatternPlayProcessRegulationReportingResearchRoleSignal PathwayStagingSystemTissuesTranscription Initiation SiteTumor Suppressor ProteinsWorkcell typehuman GATA1 proteinin vivoinsightleukemiameetingsmouse genomenovelperipheral bloodpromoterpublic health relevancerat genomeresearch studystem cell differentiationtranscription factor
项目摘要
DESCRIPTION (provided by applicant): The hematopoietic system is one of the most complex tissues and includes a number of different cell types essential for survival. This process is highly regulated by the complex interplay of signaling pathways and changing sets of transcription factors that are present in hematopoietic cells. The discovery of a new class of transcribed ultraconserved genomic regions (UCRs) that are aberrantly expressed in human leukemias, prompt us to seek whether these UCRs are differentially expressed among the specific hematopoietic lineages and whether UCRs play a role in the differentiation of hematopoietic stem cells (HPCs) into specific lineages, in particular the erythroid and megakaryocytic lineages. Using a novel UCRs microarray platform we have characterized UCRs expression at different stages of hematopoietic differentiation and identified distinctive signatures associated with particular lineages. The overall goal of this proposal is to demonstrate that transcribed UCRs are functionally relevant during hematopoiesis. To achieve this goal we propose the following specific aims: 1) Specific Aim #1: To investigate the effects of ectopic over-expression or inhibition of UCRs expression on erythrocyte and megakaryocyte lineage differentiation "in vitro" and "in vivo" by using morphology, immunophenotype, colony assays and bone marrow transplant assay experiments and 2) Specific Aim #2: To investigate whether GATA-1 regulates UCRs expression by: 1) analyzing UCRs expression after GATA-1 activation using a conditional GATA-1 cell system; 2) identifying UCRs transcription starting sites using Rapid Amplification of cDNA ends (RACE); 3) identifying GATA-1 binding sites using Chip-sequencing and 4) performing promoter functional studies. This research has the potential to identify novel regulators of hematopoiesis and may give insights into basic biology of gene expression and cell fate determination. If successful, this research will uncover an unparalleled reservoir of molecular information on ultraconserved non-coding and coding RNAs in stem cell differentiation that will be extraordinarily valuable for the field.
PUBLIC HEALTH RELEVANCE: This research has the potential to give insights into the basic mechanisms of blood formation and to identify novel regulators in this process. This new information will be extraordinarily valuable for the field. Potential benefits include: 1) direct insight into normal hematopoietic regulation will also be important to understand malfunction in leukemias and other hematologic disorders and 2) the pharmacological modulation of hematopoietic stem cells by targeting critical regulators could be used to treat a wide variety of blood cell disorders that arise from abnormalities in the red or platelet family.
描述(由申请人提供):造血系统是最复杂的组织之一,包括许多生存所必需的不同细胞类型。这个过程是高度调节的复杂的相互作用的信号转导途径和不断变化的转录因子是存在于造血细胞。人类白血病中异常表达的一类新的转录的超保守基因组区域(UCRs)的发现,促使我们寻求这些UCRs是否在特定的造血谱系中差异表达,以及UCRs是否在造血干细胞(HPCs)分化为特定谱系,特别是红系和巨核系中发挥作用。使用一种新的UCRs微阵列平台,我们已经表征了造血分化不同阶段的UCRs表达,并鉴定了与特定谱系相关的独特特征。该提案的总体目标是证明转录的UCR在造血过程中具有功能相关性。为了实现这一目标,我们提出了以下具体目标:1)具体目标#1:通过使用形态学、免疫表型、集落测定和骨髓移植测定实验,研究UCR表达的异位过表达或抑制对红细胞和巨核细胞谱系分化的“体外”和“体内”影响,以及2)具体目标#2:为了研究加塔-1是否调节UCRs的表达,通过:1)使用条件加塔-1细胞系统分析加塔-1激活后UCRs的表达; 2)使用cDNA末端快速扩增(RACE)鉴定UCRs转录起始位点; 3)使用芯片测序鉴定加塔-1结合位点和4)进行启动子功能研究。这项研究有可能确定新的造血调节因子,并可能深入了解基因表达和细胞命运决定的基础生物学。如果成功,这项研究将揭示干细胞分化中超保守的非编码和编码RNA分子信息的无与伦比的储存库,这将对该领域非常有价值。
公共卫生关系:这项研究有可能深入了解血液形成的基本机制,并在这一过程中确定新的调节剂。这一新的信息将是非常有价值的领域。潜在的好处包括:1)对正常造血调节的直接了解对于理解白血病和其它血液学病症中的功能障碍也是重要的,和2)通过靶向关键调节剂对造血干细胞的药理学调节可用于治疗由红细胞或血小板家族中的异常引起的多种血细胞病症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ramiro Garzon其他文献
Ramiro Garzon的其他文献
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Targeting the aberrant kinome-epigenome in AML
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Targeting the aberrant kinome-epigenome in AML
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- 资助金额:
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Targeting the aberrant kinome-epigenome in AML
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9055657 - 财政年份:2012
- 资助金额:
$ 19.06万 - 项目类别:
Role of the ultraconserved genomic regions (UCRs) in hematopoiesis
超保守基因组区域 (UCR) 在造血中的作用
- 批准号:
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- 资助金额:
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