权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of hematopoietic stem cell and progenitor cell proliferation by Runx1

Runx1对造血干细胞和祖细胞增殖的调节

基本信息

批准号：
8588296
负责人：
NANCY SPECK
金额：
$ 32.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8588296
关键词：
Acute Myelocytic Leukemia Age Aging Agonist Apoptosis Blood Cells Bone Marrow Transplantation Cell Lineage Cell Proliferation Cell physiology Cells Collection Commit Core-Binding Factor Cytokine Receptors DNA Binding Defect Development Disease Drug Targeting Dysmyelopoietic Syndromes Engraftment Fetal Liver Genes Goals Hematological Disease Hematopoietic Hematopoietic stem cells Incidence Life Megakaryocytes MicroRNAs Molecular Multipotent Stem Cells Mus Mutation Myelogenous Patients Phenotype Population Production Proliferating Property Proteins RUNX1 gene Refractory Anemia with Excess Blasts in Transformation Refractory anaemia with excess blasts Regulation SLAM protein Signal Transduction Staging Stem cells Study models United States base cytokine human MPL protein improved migration progenitor public health relevance stem therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the mechanisms by which loss of Runx1 in hematopoietic stem and progenitor cells alters their function, and contributes to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Inactivating mutations in RUNX1 are found in a high percentage of patients with AML of the least differentiated M0 subtype, and in MDS. MDS is a collection of blood disorders characterized by the inefficient production of one or more blood cell lineages, for which there is currently no cure aside from bone marrow transplantation. Loss of Runx1 in mice appears to recapitulate early stages of MDS, and is therefore a model for studying how impaired Runx1 function contributes to the development of this disease. We showed that loss of Runx1 causes hematopoietic stem cells and multipotent progenitors to proliferate more frequently, and that the expression of approximately 2000 genes and 40 microRNAs is altered in these populations. Here we propose to characterize the defects in HSCs and progenitors caused by Runx1 deficiency. We will examine whether genes whose expression is dysregulated in Runx1 deficient HSCs contribute to these defects. We will determine if treatment of mice with an agonist of a cytokine receptor that is under-expressed improves engraftment. Finally we will assess the contribution of several microRNAs to the engraftment defects associated with Runx1 deficiency, and their ability to cause MDS.

描述（由申请人提供）：本提案的目的是阐明造血干细胞和祖细胞中Runx 1缺失改变其功能并导致骨髓增生异常综合征（MDS）和急性髓性白血病（AML）发生的机制。RUNX1的失活突变在高比例的最低分化M0亚型AML患者和MDS中发现。MDS是一种血液疾病的集合，其特征在于一种或多种血细胞谱系的生产效率低下，目前除了骨髓移植外没有治愈方法。Runx1在小鼠中的缺失似乎重现了MDS的早期阶段，因此是研究Runx1功能受损如何促进这种疾病发展的模型。我们发现Runx1的缺失导致造血干细胞和多能祖细胞更频繁地增殖，并且在这些群体中大约2000个基因和40个microRNA的表达发生了改变。在这里，我们提出的特点Runx1缺陷引起的造血干细胞和祖细胞的缺陷。我们将研究Runx1缺陷HSC中表达失调的基因是否导致这些缺陷。我们将确定用低表达的细胞因子受体激动剂治疗小鼠是否能改善移植。最后，我们将评估几种microRNA对与Runx1缺陷相关的植入缺陷的贡献，以及它们导致MDS的能力。