Identification of Altered Molecular Signature of Down Syndrome iPS Cells

唐氏综合症 iPS 细胞分子特征改变的鉴定

• 批准号: 7941752
• 负责人: John D Crispino
• 金额: $ 49.93万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941752
• 关键词: Abnormal Platelet; Acute Lymphocytic Leukemia; Acute Megakaryocytic Leukemias; Acute leukemia; Address; Affect; Area; Blood Cells; Cardiovascular system; Cells; Child; Childhood; Clinical; Colony-forming units; Complex; Congenital Heart Defects; CpG Islands; DNA Methylation; Development; Diagnosis; Disease; Down Syndrome; Erythroid; Fetal Liver; Fetus; Fibroblasts; Gene Expression; General Population; Genes; Genotype; Germ Layers; Goals; Hematological Disease; Hematologist; Hematopoiesis; Hematopoietic; Hereditary Disease; Human; Impaired cognition; In Vitro; Incidence; Individual; Infant; Lung; Megakaryoblast; Megakaryocytes; Mesoderm; Methylation; MicroRNAs; Molecular; Molecular Profiling; Mus; Myeloproliferative disease; Natural History; Newborn Infant; Pathway interactions; Pattern; Phenotype; Platelet Count measurement; Pluripotent Stem Cells; Predisposition; Pregnancy; Proliferating; RNA; Research; Risk; Site; Specimen; Stem cells; Symptoms; Teratoma; Undifferentiated; base; craniofacial; data mining; human disease; improved; induced pluripotent stem cell; insight; leukemia; novel strategies; peripheral blood; precursor cell; progenitor; public health relevance; transcription factor; transient myeloproliferative disorder

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (14) Stem Cells and specific Challenge Topic, 14-HL-101: Develop molecular signatures for heart, vascular, lung, and blood diseases by profiling reprogrammed induced pluripotent stem cells derived from affected individuals of defined genotypes. Children with Down syndrome (DS) show a spectrum of clinical abnormalities, including a remarkable incidence of abnormal hematopoietic cell development. As many as 10% of newborns with DS show evidence of transient myeloproliferative disorder (TMD), a disease in which megakaryocyte precursor cells proliferate abnormally. Moreover, infants with TMD show a predisposition to leukemia. The natural history of hematologic abnormalities in children with DS suggests that trisomy 21 directly and functionally contributes to aberrant expansion of hematopoietic cells in the fetal liver during gestation. Consistent with this hypothesis, two studies have recently demonstrated that human fetuses with DS show a significant expansion in megakaryocyte erythroid progenitors and in both erythroid and megakaryocytic colony forming units. In order to better define the molecular differences between euploid and trisomy 21 hematopoietic progenitors, we propose to compare gene expression and methylation profiles of induced pluripotent stem cells (iPSCs) generated from individuals with and without DS. In addition, we will compare the hematopoietic differentiation potential of these two groups of iPSCs as another means to study the effect of DS on blood cell development and disease. Our specific aims are: 1) To generate and characterize trisomic and euploid iPSCs from individuals with and without Down syndrome, 2) To compare the expression of microRNAs and mRNAs in undifferentiated DS and wild-type iPSCs and hematopoietic progenitors derived from these groups of iPSCs, and 3) To characterize the epigenome of DS versus euploid iPSCs. Our long-term goal is to determine which of the microRNAs, mRNAs or methylation differences we detect in trisomy 21 cells contribute to aberrant hematopoiesis in DS. PUBLIC HEALTH RELEVANCE: This research is relevant to multiple human diseases: 1) transient myeloproliferative disease in children with DS, 2) acute leukemia in children with DS, and 3) multiple non-hematopoietic phenotypes that characterize human DS. For complex genetic diseases, such as Down syndrome, powerful new approaches, including the use of human iPSCs, are absolutely critical to improve our understanding of the molecular basis of the disease and the discovery of novel approaches to alleviate symptoms of this disease.

描述（由申请人提供）：此申请通过14-HL-101解决广泛的挑战区域（14）干细胞和特定的挑战主题：通过分析从已定义基因型的受影响的个体中得出的重编程的多能干细胞来开发心脏，血管，肺和血液疾病的分子特征。唐氏综合症（DS）儿童表现出多种临床异常，包括异常造血细胞发育的显着发生率。多达10％的具有DS的新生儿表现出瞬时骨髓增生性疾病（TMD）的证据，这是一种巨核细胞前体细胞异常增殖的疾病。此外，患有TMD的婴儿表现出对白血病的倾向。 DS儿童血液学异常的自然病史表明，妊娠期间21三体症直接并在功能上会导致胎儿肝脏中造血细胞的异常扩张。与这一假设一致，最近两项研究表明，具有DS的人类胎儿显示出巨核细胞红细胞骨祖细胞以及红细胞和巨核细胞形成单元的显着扩展。为了更好地定义多倍体和三体造血祖细胞之间的分子差异，我们建议比较由有或没有DS的个体产生的诱导多能干细胞（IPSC）的基因表达和甲基化谱。此外，我们将将这两组IPSC的造血分化潜力比较，作为研究DS对血细胞发育和疾病的影响的另一种手段。我们的具体目的是：1）生成和表征来自和不唐氏综合症患者的三聚体和多倍型IPSC，2）比较在未分化的DS和野生型IPSC和野生型iPSC，以及由IPSC epscs和3）epsemose epepiles的表达中进行比较。我们的长期目标是确定我们在21个三体细胞中检测到的microRNA，mRNA或甲基化差异，导致DS中异常的造血。 公共卫生相关性：这项研究与多种人类疾病有关：1）DS儿童的短暂性骨髓增生性疾病，2）DS患者的急性白血病，以及3）多种表征人类DS的多种非骨质型表型。对于复杂的遗传疾病，例如唐氏综合症，包括使用人IPSC在内的强大新方法，对于提高我们对疾病分子基础的理解以及发现减轻这种疾病症状的新方法至关重要。