Transcription regulation in hematopoiesis

造血转录调控

• 批准号: 9294151
• 负责人: Li Chai
• 金额: $ 45.02万
• 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/9294151
• 关键词: Autologous; Blood Cells; Blood Transfusion; CD34 gene; Cell Count; Cell Transplantation; Cell Transplants; Cell division; Cells; Cellular Assay; Cellular biology; Complex; Data; Deacetylase; Development; Engineering; Epigenetic Process; Funding; Gene Targeting; Gene-Modified; Genes; HDAC4 gene; HOXA9 gene; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; 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; Pharmacology; Play; Population; Process; Property; Proteins; Reporting; Repression; Role; Source; Technology; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Transcriptional Activation; Transcriptional Activation Domain; Transcriptional Regulation; Transfusion; Transplantation; Umbilical Cord Blood; Zinc Fingers; base; clinical application; embryonic stem cell; epigenetic memory; experimental study; gene therapy; genetic approach; genome editing; in vivo; insight; member; mutant; new technology; novel; programs; self-renewal; small molecule; 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） 细胞治疗，包括造血干/祖细胞（HSPC）移植，是治疗的重要组成部分。 输血医学实践。脐带血可以作为 HSPC 供体的绝佳替代来源； 然而，它的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取得的进展 对于体内造血系统，如何调节控制造血系统自我更新的因素知之甚少。 HSPC 离体。与胚胎干 (ES) 细胞不同，HSPC 在培养物中的扩增速度一般为 以“干性”为代价。我们假设 HSPC 的命运受到关键转录因子的控制， 在 HSPC 离体扩增过程中下调。转录因子通过以下方式维持 HSPC 特性： 在细胞分裂过程中为表观遗传记忆添加书签。识别这些转录因子对于 离体HSPC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 细胞特性方面发挥着至关重要的作用。 SALL4也是调节的关键因素 人类正常造血功能，可用于扩大脐带血HSPC群体。的机制 SALL4在正常造血过程中，至少部分是通过其转录激活结构域及其相互作用 与 MLL 表观遗传复合体。根据我们的初步研究，我们提出了 SALL4 转录 激活功能对于 CD34+ HSPC 扩增以及发现新的药理学工具非常重要 增强其转录激活特性可能会导致新的 HSPC 扩增技术。我们 提出了以下具体目标： 具体目标 I：描述 SALL4 的功能角色 HSPC 扩增中的转录激活结构域。具体目标二：确定其分子机制 HSPC 扩增中的 SALL4 转录激活域。具体目标三：筛选和鉴定小分子 增强 SALL4 介导的 HSPC 扩增的化合物。我们提出的实验一旦完成，就不会 不仅可以为我们提供对HSPC生物学的见解，还可以为我们提供新型的小分子药物 HSPC 扩展的目的。