Transcription regulation in hematopoiesis

造血转录调控

• 批准号: 9072499
• 负责人: Li Chai
• 金额: $ 45.56万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9072499
• 关键词: Autologous; Blood Cells; Blood Transfusion; CD34 gene; Cell Count; Cell Transplants; Cell division; Cells; Cellular Assay; Cellular biology; Complex; Data; Deacetylase; Development; Engineering; Epigenetic Process; Funding; Gene Targeting; Gene-Modified; Genes; HOXA9 gene; Hematopoiesis; Hematopoietic; Hematopoietic System; Histone Deacetylase; Human; In Vitro; Lead; Length; Maintenance; Mediating; Medicine; Mixed-Lineage Leukemia; Modeling; Molecular; Myeloid-Lymphoid Leukemia Protein; N-terminal; Nucleosomes; PTEN gene; Patients; Peptides; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; Reporting; Repression; Role; Source; Stem cell transplant; Stem cells; Technology; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Regulation; Transfusion; Transplantation; Umbilical Cord Blood; Zinc Fingers; base; clinical application; embryonic stem cell; epigenetic memory; gene therapy; genetic approach; genome editing; in vivo; insight; member; mutant; new technology; novel; programs; research study; self-renewal; small molecule; stem; stemness; tool; transcription factor

Project Summary (Project 2) Cellular therapy, including hematopoietic stem/progenitor cell (HSPC) transplant, is a critical part of transfusion medicine practice. Umbilical cord blood can be an excellent alternative HSPC donor source; however its use is severely constrained by the limited HSPC numbers in one single cord blood unit. Despite our progress in understanding the molecular factors that support the self-renewal and differentiation of the hematopoietic system in vivo, less is known on how to modulate the factors that govern the self-renewal of HSPCs ex vivo. Unlike in the case of embryonic stem (ES) cells, expansion of HSPC in culture in general is at the expense of “stemness”. We hypothesize that the HSPC fate is governed by key transcription factors, which are down-regulated during HSPC ex vivo expansion. Transcription factors maintain the HSPC identity by bookmarking the epigenetic memories during cell division. Identifying these transcription factor(s) is critical for the development of ex vivo HSPC expansion technology. ES cell gene SALL4 is a zinc finger transcription factor. It plays vital roles in the maintenance of ES cell properties. SALL4 is also a key factor in regulating human normal hematopoiesis, and can be used to expand cord blood HSPC population. The mechanism(s) of SALL4 in normal hematopoiesis, at least in part, is through its transcription activation domain and its interaction with the MLL epigenetic complex. Based on our preliminary studies, we propose the SALL4 transcription activation function is important for CD34+ HSPC expansion, and discovery of novel pharmacological tools to enhance its transcription activation property could potentially lead to new HSPC expansion technology. We have proposed the following specific aims: Specific Aim I: Characterize the functional role(s) of SALL4 transcription activation domain in HSPC expansion. Specific Aim II: Determine the molecular mechanism of SALL4 transcription activation domain in HSPC expansion. Specific Aim III: Screen and identify small molecule compounds to enhance SALL4 mediated HSPC expansion. Our proposed experiments, once completed, not only can offer us insights on HSPC biology, but also provide us with novel small molecule drugs for the purpose of HSPC expansion.

项目概要（项目2） 细胞疗法，包括造血干/祖细胞（HSPC）移植，是造血干/祖细胞移植的关键部分。 输血医学实践。脐带血是一种很好的替代HSPC供体来源; 然而，其使用受到单个脐带血单位中有限的HSPC数量的严重限制。尽管 我们在理解支持自我更新和分化的分子因素方面的进展， 尽管在体内的造血系统中，对如何调节支配造血系统自我更新的因子知之甚少。 离体HSPC。与胚胎干（ES）细胞的情况不同，HSPC在培养物中的扩增一般在200 - 300 μ g/ml。 为“sterness”付出代价。我们假设HSPC的命运是由关键的转录因子， 在HSPC离体扩增期间下调。转录因子通过以下方式维持HSPC身份： 标记细胞分裂时的表观遗传记忆识别这些转录因子对于 体外HSPC扩增技术的发展。ES细胞基因SALL 4是一个锌指转录因子， 因子它在维持ES细胞特性中起着重要作用。SALL 4也是调节 人正常造血，并可用于扩增脐带血HSPC群体。机制 SALL 4在正常造血中，至少部分是通过其转录激活结构域及其相互作用 MLL表观遗传复合体基于我们的初步研究，我们提出了SALL 4转录本 活化功能对于CD 34 + HSPC扩增是重要的，并且发现了新的药理学工具， 增强其转录激活特性可能潜在地导致新的HSPC扩增技术。我们 提出了以下具体目标：具体目标一：说明小武器和轻武器的职能作用4 HSPC扩增中的转录激活结构域。具体目标II：确定 HSPC扩增中的SALL 4转录激活结构域。具体目标III：筛选和鉴定小分子 化合物以增强SALL 4介导的HSPC扩增。我们提出的实验一旦完成， 不仅可以为我们提供HSPC生物学方面的见解，还可以为我们提供新型小分子药物， HSPC扩展的目的。