Regulation of hematopoiesis by CUX1

CUX1 对造血的调节

基本信息

批准号：
10418712
负责人：
Megan McNerney
金额：
$ 39.9万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418712
关键词：
Acute leukemia Address Anemia Biological Assay Biology Blood Blood Cells Blood Platelets Cell Cycle Cell Cycle Regulation Cells Chromosome 7 Chromosome Deletion Chromosome abnormality Clinical Cyclins Defect Development Disease Down-Regulation Drosophila genus Dysmyelopoietic Syndromes Dysplasia Erythroblasts Erythrocytes Erythroid Erythropoiesis Future Genes Genetic Genetic Transcription Genomic approach Genomics Goals Health Care Costs Hematopoiesis Hematopoietic stem cells Human In Vitro Knowledge Laboratories Leukocytes Megakaryocytes Molecular Morbidity - disease rate Mus Mutation Myelogenous Myeloproliferative disease Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Prevalence Production Prognosis Public Health Quality of life Recurrence Regulation Reporting Research Personnel Risk Role Signal Transduction Transcriptional Activation Transcriptional Regulation United States Work chromosome 7 loss chromosome 7q loss cytopenia design effectiveness evaluation erythroid differentiation exhaustion functional genomics granulocyte homeodomain improved in vivo in vivo Model inhibitor innovation kinase inhibitor knock-down mortality mouse model myelodysplastic anemia new therapeutic target novel novel therapeutic intervention novel therapeutics preclinical study prevent progenitor self-renewal stem cell function stem cell homeostasis stem cell proliferation transcription factor transcriptome

项目摘要

PROJECT SUMMARY Myelodysplastic syndromes (MDS) are disorders of hematopoietic stem and progenitor cells (HSPCs) that results in cytopenias, however, the genetic causes of this dysfunctional hematopoiesis remain unclear. Almost all patients suffer anemia, a major cause of morbidity, mortality, and health care costs. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common cytogenetic abnormality in MDS and carries a poor prognosis. We identified CUX1, a homeodomain-containing transcription factor encoded on 7q, to be frequently inactivated in myeloid diseases. We reported that CUX1 has highly conserved regulatory functions in both human and Drosophila blood cells. CUX1 inactivating mutations have since been reported in MDS and are independently associated with a poor prognosis. We have now generated an innovative Cux1 knockdown mouse model. Cux1-knockdown mice develop a spontaneous myeloproliferative disorder with many features of human MDS, including megakaryocyte, granulocyte, and erythroid dysplasia, and a fatal anemia. Preliminary studies indicate that Cux1 knockdown impacts multiple stages of hematopoiesis, disrupting early HSPC functions as well as blocking late stages of erythroid development. A major knowledge gap, which this proposal is designed to address, is the mechanism by which CUX1 regulates normal hematopoiesis. The overall objective is to determine the transcriptional role for CUX1 in normal HSPCs and erythroid progenitors and the pathways downstream of CUX1 haploinsufficiency that block erythroid differentiation. Aim 1: Hypothesis – CUX1 is a transcriptional regulator of HSPC homeostasis conserved in mice and humans. We will take advantage of our novel mouse model for in vivo analyses of Cux1 regulation of HSPC quiescence, proliferation, and differentiation. We will perform complementary studies with primary human HSPCs to establish the translational relevance of this work. We will capitalize on leading-edge functional genomics approaches to identify CUX1 genomic targets in human HSPCs. Aim 2: Hypothesis – CUX1 promotes erythroblast cell cycle exit necessary for terminal differentiation by repressing PI3K signaling. We will identify the specific developmental stage of erythropoiesis disrupted by Cux1 knockdown in mice. We will determine the conserved role for CUX1 in human red cell development, and the pathways induced by CUX1 deficiency that disrupt erythropoiesis. Our functional and genomic analyses of primary human HSCs will dovetail with in vivo assays to elucidate the critical role for CUX1 transcriptional regulation of normal erythropoiesis. This work will have a positive impact on the fields of HSC and erythroid biology by identifying the molecular mechanism by which CUX1 regulates normal HSC functions and the pathogenesis of CUX1-deficiency in disease states. Our studies will reveal novel therapeutic targets for treating anemia in MDS patients and a murine model of MDS for preclinical studies.

项目摘要骨髓增生综合征（MDS）是造血茎和祖细胞（HSPC）的疾病然而，导致细胞质的结果，这种功能障碍造血的遗传原因尚不清楚。几乎所有患者都患有贫血，这是发病率，死亡率和医疗保健费用的主要原因。零件或全部删除 7 [-7/del（7q）染色体]是MDS中常见的细胞遗传学异常，预后不良。我们确定的Cux1是一种在7Q上编码的含同源域的转录因子，经常被灭活髓样疾病。我们报道Cux1在人类和果蝇血细胞。此后，CUX1在MDS中报道了灭活突变，并且是独立的与预后不良有关。现在，我们已经生成了创新的CUX1敲低鼠标模型。 Cux1 knockdown小鼠患有赞助的骨髓增生障碍，具有许多人类MD的特征，包括巨核细胞，粒细胞和红细胞发育不良，以及致命的贫血。初步研究表明CUX1敲低影响造血的多个阶段，使早期HSPC的作用为并阻止红细胞发育的后期阶段。该提案设计的主要知识差距要解决的是CUX1调节正常造血的机制。总体目标是确定CUX1在正常HSPC和红细胞祖细胞和途径中的转录作用 Cux1单倍性的下游阻断了红细胞分化。目标1：假设 - CUX1是一个在小鼠和人类中保存HSPC稳态的转录调节剂。我们将利用我们的优势用于HSPC静止，增殖和CUX1调节体内分析的新型小鼠模型分化。我们将对主要人类HSPC进行完整的研究以建立这项工作的翻译相关性。我们将利用领先的功能基因组学方法识别人类HSPC中的CUX1基因组靶标。 AIM 2：假设 - CUX1促进红细胞细胞周期通过抑制PI3K信号传导所需的终端分化所需的退出。我们将确定特定的小鼠CUX1敲低破坏了红细胞生成的发育阶段。我们将确定 CUX1在人红细胞发育中配置了角色，以及由CUX1缺乏引起的途径破坏红细胞生成。我们对原代人HSC的功能和基因组分析将与体内相互吻合阐明正常红细胞生成的CUX1转录调控的关键作用的测定。这项工作将通过确定通过确定分子机制的HSC和红细胞生物学领域的积极影响 CUX1调节疾病状态中CUX1缺陷的正常HSC功能和发病机理。我们的研究将揭示用于治疗MDS患者贫血的新型治疗靶标和MDS的鼠模型用于临床前研究。