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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

基本信息

批准号：
10183274
负责人：
NANCY SPECK
金额：
$ 37.32万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-21 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183274
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

项目摘要

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.

项目摘要造血干细胞和祖细胞（HSPC）从特化的胚胎中的内皮细胞称为生血内皮（HE）。的转录因子Runx1是造血细胞特异性表达所必需的。内皮细胞和内皮细胞向HSPC的转变。但如何 Runx1这样做是很难理解的。我们的目标是应用系统生物学造血调控转录调控网络的研究进展内皮特异性，包括Runx1的作用，额外的转录与Runx1合作的因素，以及调节事件的顺序，推动这一进程。这些研究不仅会增加我们对 HSPC形成的正常发育过程，但将有助于指导试图从内皮细胞，ES，或iPS细胞用于治疗疾病。在目标1中，我们将识别Runx1目标胚胎内皮细胞中能够对Runx1应答的基因，和检查全基因组染色质修饰和基因表达变化，当Runx1结合其靶基因时发生。在目标2中，我们将开发一种先进的用图论方法识别与Runx1协同作用的胚胎关键转录因子内皮细胞以诱导HE并形成血液。我们将通过以下方式验证候选TF 确定它们与Runx1合作诱导胎儿内皮细胞的能力，经历内皮细胞向HSPC的转变并形成血液。