Functions of the TG-Interacting Transcription Factor (TGIF) in Hematopoiesis
TG 相互作用转录因子 (TGIF) 在造血中的功能
基本信息
- 批准号:7659770
- 负责人:
- 金额:$ 12.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-25 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAffectAllelesArtsBiologicalBiological AssayBone MarrowBone Marrow CellsCell CycleCell LineCell physiologyCellsClinicalCodeColony-forming unitsComplementDataDefectDevelopmentDiagnosisDiseaseDoctor of PhilosophyEquilibriumExperimental DesignsExposure toFellowshipGeneticGenetic TranscriptionGrowthHL60HematopoiesisHematopoietic stem cellsHoloprosencephalyImmunologyIn VitroInstructionInvestigationKnock-outKnockout MiceKnowledgeLeadLeukemic CellMapsMediatingMedicineMentorsMentorshipMicrobiologyModelingMolecularMusMutationMyelogenousMyeloid Progenitor CellsPathogenesisPathway interactionsPatientsPediatricsPhenotypePlayPrincipal InvestigatorProliferatingRNARelapseRelative (related person)ResidenciesRoleSecondary toSeriesSignal TransductionSpleenStagingStem cellsStructureTamoxifenTechniquesTestingTrainingTransforming Growth FactorsTransplantationTretinoinUniversitiesbasecareercellular transductionchemotherapeutic agentchemotherapydesignflexibilityin vivoinsightleukemogenesismouse modelmutantoverexpressionprognostic indicatorprogramsresearch studyself-renewalstem cell biologytranscription factor
项目摘要
DESCRIPTION (provided by applicant): We have discovered that quantitative expression of the stem cell expressed transcriptional represser Transforming-growth-interfering factor (TGIF) is the most discriminating and powerful predictor of patient survival identified in acute myelogenous leukemia (AML). Lower levels of TGIF correlated with shorter survival, whereas higher levels predicted longer survival (p=0.00001). To understand the biological basis for our clinical finding, we investigated TGIF's function in myeloid progenitor cell lines and in a Tg/'f knockout mouse model. TGIF knockdown in myeloid progenitor cell lines, such as HL60, resulted in significant growth inhibition, a relative differentiation block, and disruption of the myeloid transcription program. Analysis of hematopoietic stem cell (HSC) function in Tg/7-null mice showed that the HSCs produced fewer colony- forming units and had a growth advantage compared to wild-type HSCs in competitive transplant studies. These data suggest that Tg/f knockout may alter the balance between the key HSC functions of quiescence, differentiation and self-renewal. We thus hypothesize that Tgif plays a fundamental regulatory role in HSC function and will examine this hypothesis by 1) defining more thoroughly the role of Tgif'm HSC and progenitor cell function; 2) determining the cellular basis of Tgif's effects on HSCs; and 3) determining the molecular basis of Tgif's effects on HSCs. These aims will be carried out in a series of experiments using a variety of standard and state-of-the-art molecular techniques, including limiting dilution competitive repopulation analysis, serial transplantation, in vivo cell cycle analysis, and structure-function characterizations using naturally occurring TGIF mutations and ex vivo HSC transduction. In addition to the Tgif knockout model currently in use, we will also employ a new conditional Tgif knockout allele, which will offer us great flexibility in our experimental design. This proposal also outlines a plan designed to help the candidate develop a successful career in academic medicine. The candidate has a Ph.D. in Microbiology and Immunology from Vanderbilt University and has completed residency training in Pediatrics and fellowship training in Genetics. The candidate will expandhis knowledge of hematopoiesis and leukemogenesis under the mentorship of Drs. Stephen Brandt and Scott Hiebert. A mentoring committee will provide added guidance at regular intervals. RELEVANCE (See instructions): In acute leukemias, including AML, the normal balance between quiescence, self-renewal and differentiation of HSCs is disrupted. Our preliminary data suggest that Tgif may regulate this balance and that it also has a clinical role as a prognostic indicator in AML. Thus, our investigations of how Tgif regulates key HSC functions will provide new insights into HSC biology as well as increase our understanding of AML pathogenesis, leading to better diagnosis and treatment of this devastating disease.
描述(由申请人提供):我们发现干细胞表达的转录抑制因子转化生长干扰因子(TGIF)的定量表达是急性髓性白血病(AML)中鉴定的患者存活率的最具鉴别力和最有力的预测因子。较低水平的TGIF与较短的生存期相关,而较高的水平预测较长的生存期(p=0.00001)。为了理解我们临床发现的生物学基础,我们研究了TGIF在骨髓祖细胞系和Tg/f敲除小鼠模型中的功能。TGIF敲低髓系祖细胞系,如HL 60,导致显着的生长抑制,相对分化阻滞,髓系转录程序的破坏。Tg/7缺失小鼠中造血干细胞(HSC)功能的分析显示,与竞争性移植研究中的野生型HSC相比,HSC产生更少的集落形成单位并且具有生长优势。这些数据表明,Tg/f基因敲除可能会改变静止,分化和自我更新的关键HSC功能之间的平衡。因此,我们假设Tgif在HSC功能中起着基本的调节作用,并将通过以下方式检验该假设:1)更彻底地定义Tgif在HSC和祖细胞功能中的作用; 2)确定Tgif对HSC作用的细胞基础;和3)确定Tgif对HSC作用的分子基础。这些目标将在一系列实验中使用各种标准和最先进的分子技术,包括有限稀释竞争性再增殖分析,连续移植,体内细胞周期分析和结构功能表征,使用天然存在的TGIF突变和离体HSC转导。除了目前使用的Tgif敲除模型,我们还将采用一种新的条件性Tgif敲除等位基因,这将为我们的实验设计提供极大的灵活性。该提案还概述了旨在帮助候选人在学术医学领域发展成功职业生涯的计划。候选人拥有博士学位。在微生物学和免疫学从范德比尔特大学,并已完成住院医师培训在儿科和奖学金培训在遗传学。候选人将在Stephen Brandt和Scott Hiebert博士的指导下扩展他的造血和白血病发生知识。指导委员会将定期提供额外的指导。相关性(参见说明):在急性白血病(包括AML)中,HSC的静止、自我更新和分化之间的正常平衡被破坏。我们的初步数据表明,Tgif可以调节这种平衡,它也有一个临床作用作为AML的预后指标。因此,我们对Tgif如何调节关键HSC功能的研究将为HSC生物学提供新的见解,并增加我们对AML发病机制的理解,从而更好地诊断和治疗这种毁灭性疾病。
项目成果
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RIZWAN HAMID其他文献
RIZWAN HAMID的其他文献
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