Effect of MKL1 on murine embryonic megakaryocytopoiesis
MKL1对小鼠胚胎巨核细胞生成的影响
基本信息
- 批准号:7918736
- 负责人:
- 金额:$ 4.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-08 至 2011-09-07
- 项目状态:已结题
- 来源:
- 关键词:Acute Megakaryocytic LeukemiasAnimal ModelBiological AssayCell Culture TechniquesCellsChromosomal translocationChromosomes, Human, Pair 1DataDevelopmentDiseaseDominant-Negative MutationES Cell LineEmbryoEtiologyGenesGenetic TranscriptionGoalsHematopoiesisHematopoieticHumanHuman Cell LineIndividualInfantInvestigationKnockout MiceLengthLightMalignant - descriptorMegakaryocyte ProliferationMegakaryocytesMusMutationNeonatalPathogenesisPatientsPhenotypePreparationProteinsRegulationResearchRoleSystemTestingTranslatingWorkbasecancer typeembryonic stem cellfusion geneinsightleukemiamouse modelmyocardinsmall hairpin RNAstemstem cell differentiationtranscription factor
项目摘要
DESCRIPTION (provided by applicant): Acute Megakaryoblastic Leukemia is characterized by the blocked differentiation and improper proliferation of megakaryocytes. The 1;22 chromosomal translocation that has been found to associate with AMKL infants implicates the fusion gene product in leukemiogenesis. The fusion gene consists of full length MKL1 fused in frame and downstream of RBM15. Our lab focuses on the normal and aberrant functioning of MKL1, a myocardin related transcription factor, in the regulation of megakaryocytopoiesis. We propose to study MKL1 in murine embryonic stem (ES) cells in an attempt to mimic developmental hematopoiesis and further understand the disease in the neonatal system. We will test if enforced and misexpression of MKL1 has an effect on megakaryocyte differentiation. To test the hypothesis that enforced expression of MKL1 promotes mouse ES cell differentiation we will develop an inducible MKL1 ES cell line and analyze it for MK differentiation. In addition, we will conduct studies to determine the requirement for MKL1 and/or MKL2 in megakaryocyte differentiation. To do this, we will construct inducible ES cell clones expressing a dominant negative MKL1 or shRNA against MKL1 and/or MKL2. To determine the effects on megakaryocytopoiesis we will use CFU-Mk (a functional assay), flow cytometric analysis (a phenotypic assay), and cytospin preparations (a morphological assay). Concurrent with the cell culture investigations, we will conduct a more hematopoietic focused analysis of MKL1-/- mice and further manipulate the animal model to discern the role of MKL1 in megakaryocytopoiesis. The goal of the work is to create a mouse system that can be translated into human cells for the study of AMKL caused by the 1;22 translocation. This transition will create opportunities for therapy based research and ultimately more informed and precise treatments for afflicted individuals.
描述(申请人提供):急性巨核细胞白血病的特征是巨核细胞分化受阻和不正常的增殖。已发现与AMKL婴儿相关的1;22染色体易位与白血病的发生有关。融合基因由融合在RBM15框架内和下游的全长MKL1组成。我们的实验室主要研究MKL1的正常和异常功能,MKL1是一种肌钙蛋白相关的转录因子,在巨核细胞生成的调节中。我们建议研究小鼠胚胎干细胞(ES)中的MKL1,以试图模拟发育中的造血,并进一步了解新生儿系统中的疾病。我们将测试MKL1的强制和错误表达是否对巨核细胞分化有影响。为了验证增强表达MKL1促进小鼠ES细胞分化的假设,我们将建立一个可诱导的MKL1 ES细胞系,并对其进行MK分化分析。此外,我们还将进行研究,以确定巨核细胞分化过程中对MKL1和/或MKL2的需求。为此,我们将构建可诱导的ES细胞克隆,表达针对MKL1和/或MKL2的显性负向MKL1或shRNA。为了确定对巨核细胞生成的影响,我们将使用CFU-Mk(一种功能分析)、流式细胞仪分析(一种表型分析)和细胞旋体制剂(一种形态分析)。在细胞培养研究的同时,我们将对MKL1-/-小鼠进行更注重造血的分析,并进一步操纵动物模型以识别MKL1在巨核细胞生成中的作用。这项工作的目标是创造一种可以翻译成人类细胞的小鼠系统,用于研究1;22易位引起的AMKL。这一过渡将为以治疗为基础的研究创造机会,并最终为患病个人提供更知情和更精确的治疗。
项目成果
期刊论文数量(0)
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Elenoe C. Smith其他文献
Elenoe C. Smith的其他文献
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{{ truncateString('Elenoe C. Smith', 18)}}的其他基金
Effect of MKL1 on murine embryonic megakaryocytopoiesis
MKL1对小鼠胚胎巨核细胞生成的影响
- 批准号:
7690263 - 财政年份:2008
- 资助金额:
$ 4.14万 - 项目类别:
Effect of MKL1 on murine embryonic megakaryocytopoiesis
MKL1对小鼠胚胎巨核细胞生成的影响
- 批准号:
7547327 - 财政年份:2008
- 资助金额:
$ 4.14万 - 项目类别:
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