Mechanisms of endothelial-to-hemogenic transition mediated by Runx1

Runx1介导的内皮细胞向造血细胞转变的机制

• 批准号: 9922673
• 负责人: NANCY SPECK
• 金额: $ 38.08万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-21 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922673
• 关键词: Address; Algorithms; Binding; Biological; Blood; Blood Cells; Bone Marrow Transplantation; Cell Differentiation process; Cell Lineage; Cells; Chromatin; Collaborations; Competence; Data; Development; Developmental Process; Disease; Ectopic Expression; Embryo; Endothelial Cells; Endothelium; Epigenetic Process; Event; Gene Expression; Genes; Genetic Transcription; Goals; Graph; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Immune; In Vitro; Life; Malignant - descriptor; Mediating; Methods; Molecular; Non-Malignant; Patients; Population; Problem Solving; Procedures; Process; Role; Savings; Site; Source; System; Systems Biology; Testing; Time; Transitional Cell; base; chromatin modification; computerized tools; design; endothelial stem cell; epigenome; fetal; genome-wide; hemogenic endothelium; improved; induced pluripotent stem cell; novel; novel strategies; predictive tools; prospective; screening; tool; transcription factor; transcriptome

Project Summary Hematopoietic stem and progenitor cells (HSPCs) differentiate from specialized endothelial cells in the embryo called hemogenic endothelium (HE). The transcription factor Runx1 is required for the specification of hemogenic endothelium and for the endothelial to HSPC transition to occur. However, how Runx1 does so is poorly understood. Our goal is to apply systems biology approaches to study the transcriptional regulatory network controlling hemogenic endothelial specification, including the role of Runx1, additional transcription factors that cooperate with Runx1, and the order of regulatory events that promote the process. These studies will not only increase our understanding of the normal developmental process of HSPC formation, but will help guide attempts to generate hematopoietic stem cells (HSCs) from endothelial cells, ES, or iPS cells for the treatment of disease. In Aim 1, we will identify Runx1 target genes in embryonic endothelial cells that are competent to respond to Runx1, and examine the genome-wide chromatin modifications and gene expression changes that take place when Runx1 binds its target genes. In Aim 2, we will develop an advanced graph-theoretic method to identify key TFs that cooperate with Runx1 in embryonic endothelial cells to induce HE and form blood. We will validate the candidate TFs by determining their ability to cooperate with Runx1 to induce fetal endothelial cells to undergo endothelial to HSPC transition and form blood.

项目摘要 造血茎和祖细胞（HSPC）与专业区分开 胚胎中的内皮细胞称为疟疾内皮（HE）。这 转录因子runx1是血液形成规格所必需的 内皮和内皮到HSPC过渡的发生。但是，如何 Runx1这样做的理解很少。我们的目标是应用系统生物学 研究转录调节网络控制血液生成的方法 内皮规范，包括runx1的作用，附加转录 与Runx1合作的因素以及监管事件的顺序 促进过程。这些研究不仅会增加我们对 HSPC形成的正常发展过程，但将有助于指导 尝试从内皮细胞ES，ES， 或IPS细胞治疗疾病。在AIM 1中，我们将确定Runx1目标 胚胎内皮细胞中有能力响应runx1的基因， 检查全基因组染色质的修饰和基因表达改变， 当Runx1结合其靶基因时发生。在AIM 2中，我们将开发一个先进的 图理论方法识别与enbryonic中Runx1合作的关键TF 内皮细胞诱导他并形成血液。我们将通过 确定他们与Runx1合作以诱导胎儿内皮细胞的能力 经过内皮到HSPC过渡并形成血液。