Transcription regulation in hematopoiesis

项目总结(项目2) 细胞治疗，包括造血干细胞/祖细胞(HSPC)移植，是 输血医学实践。脐带血可以作为HSPC良好的供体来源； 然而，它的使用受到单个脐带血单位中HSPC数量有限的严重限制。尽管 我们在理解支持细胞自我更新和分化的分子因素方面的进展 在体内的造血系统中，人们对如何调节控制干细胞自我更新的因素知之甚少。 体外培养的HSPC。与胚胎干细胞不同的是，HSPC在培养中的扩增通常是 “干性”的代价。我们假设HSPC的命运由关键的转录因子决定，这些转录因子 在HSPC体外扩增过程中表达下调。转录因子通过以下方式维持HSPC的同源性 给细胞分裂过程中的表观遗传记忆加书签。识别这些转录因子(S)对于 HSPC体外扩增技术的发展。ES细胞基因SALL4是锌指转录 因素。它在维持ES细胞特性方面起着至关重要的作用。SALL4也是调控的一个关键因素 人正常造血，可用于扩增脐血HSPC人群。机制(S) SALL4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来实现的 与MLL表观遗传复合体。在我们初步研究的基础上，我们提出了SALL4转录 激活功能对CD34+HSPC的扩增和新的药理工具的发现具有重要意义 增强其转录激活特性可能导致新的HSPC扩增技术。我们 提出了以下具体目标：具体目标一：明确SALL4的功能作用(S) HSPC扩增中的转录激活结构域。特定目标II：确定其分子机制 HSPC扩增中的SALL4转录激活结构域。具体目标三：筛选和鉴定小分子 化合物促进SALL4介导的HSPC扩增。我们提议的实验一旦完成，就不会 不仅可以为我们提供有关HSPC生物学的见解，还可以为我们提供新的治疗HSPC的小分子药物 HSPC扩容的目的。

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.