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

• 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
• 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

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）：该提案的目的是阐明造血茎和祖细胞中Runx1损失的机制改变其功能，并有助于骨髓增生综合征（MDS）和急性骨髓性白血病（AML）的发展。在RUNX1中的灭活突变是在很大比例的M0亚型和MDS中的AML患者中发现的。 MDS是血液疾病的集合，其特征是一种或多种血细胞谱系效率低下，除骨髓移植外，目前尚无治愈方法。小鼠中RUNX1的损失似乎概括了MD的早期阶段，因此是研究RUNX1功能受损的模型，如何有助于这种疾病的发展。我们表明，RUNX1的损失会导致造血干细胞和多能祖细胞更频繁地增殖，并且在这些人群中，大约2000个基因和40个microRNA的表达发生了变化。在这里，我们建议表征由Runx1缺乏引起的HSC和祖细胞中的缺陷。我们将检查表达在RUNX1缺陷HSC中失调的基因是否有助于这些缺陷。我们将确定用不足表达的细胞因子受体的激动剂治疗小鼠是否会改善植入。最后，我们将评估几种microRNA对与Runx1缺乏症相关的植入缺陷的贡献及其引起MD的能力。