MOLECULAR CORRELATES OF HOXB4 FUNCTION

HOXB4 功能的分子关联

• 批准号: 6946264
• 负责人: BERNARD G FORGET
• 金额: $ 25.09万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946264
• 关键词: RNA interference; binding sites; cell differentiation; cell proliferation; chromatin immunoprecipitation; flow cytometry; gene expression; gene expression profiling; genetically modified animals; green fluorescent proteins; hematopoiesis; hematopoietic stem cells; homeobox genes; laboratory mouse; microarray technology; protein protein interaction; recombinant proteins; yeast two hybrid system

Hematopoeitic stem cells comprise a very small faction of bone marrow mononuclear cells, which retain the capacity for self-renewal as well as controlled differentiation into all of the cellular elements of the peripheral blood. The molecular signals that confer the stem cell phenotype and the mechanisms that control stem cell proliferation and differentiation are not completely understood. The homeobox gene HoxB4 is expressed in hematopoietic stem/progenitor cells but not in more differentiated cells. Studies by a number of different investigators have shown that enforced expression of HoxB4 in hematopoietic stem cells leads to enhancement of their ability to expand, both in vivo and in vitro, without inducing adverse events such as the development of leukemia. The overall research goal of this proposal is to investigate the molecular mechanisms of action of HoxB4 in stem cell expansion, using currently emerging tools for genomic scale analysis. These analyses will include a variety of technologies, including gene transfer followed by induced expression of the transferred gene(s), gene expression profiling using microarrays, chromatin immunoprecipitation followed by large scale screening to identify HoxB4 binding sites in genomic DNA, study of protein-protein interactions, functional studies of recombinant chimeric fusion proteins, inhibition of gene expression by RNAi and protein uptake experiments.

造血干细胞包括一个很小的骨髓单核细胞派别，该派别保留了自我更新的能力以及控制分化为外围血液的所有细胞元素的能力。尚未完全了解赋予干细胞表型的分子信号以及控制干细胞增殖和分化的机制。同源基因基因HOXB4在造血干/祖细胞中表达，但在更分化的细胞中不表达。通过多个不同的研究 研究人员表明，在造血干细胞中强迫HOXB4的表达导致增强其在体内和体外扩展的能力，而不会引起不良事件，例如白血病的发展。该建议的总体研究目标是使用当前新兴的基因组量表分析工具研究HOXB4在干细胞扩展中的作用分子机制。 These analyses will include a variety of technologies, including gene transfer followed by induced expression of the transferred gene(s), gene expression profiling using microarrays, chromatin immunoprecipitation followed by large scale screening to identify HoxB4 binding sites in genomic DNA, study of protein-protein interactions, functional studies of recombinant chimeric fusion proteins, inhibition of gene expression by RNAi and protein吸收实验。