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

基本信息

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
项目类别：
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

项目摘要

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）：本申请涉及广泛的挑战领域（14）干细胞和特定挑战主题，14-HL-101：通过分析衍生的重编程诱导多能干细胞，开发心脏、血管、肺和血液疾病的分子特征来自具有确定基因型的受影响个体。患有唐氏综合症（DS）的儿童表现出一系列临床异常，包括造血细胞发育异常的显着发生率。多达 10% 的 DS 新生儿表现出短暂性骨髓增殖性疾病 (TMD) 的症状，这是一种巨核细胞前体细胞异常增殖的疾病。此外，患有 TMD 的婴儿有患白血病的倾向。 DS 儿童血液学异常的自然史表明，21 三体在妊娠期间直接和功能性地导致胎儿肝脏中造血细胞的异常扩张。与这一假设相一致的是，最近的两项研究表明，患有 DS 的人类胎儿表现出巨核细胞红系祖细胞以及红系和巨核细胞集落形成单位的显着扩张。为了更好地定义整倍体和 21 三体造血祖细胞之间的分子差异，我们建议比较患有和不患有 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，我们将比较这两组iPSC的造血分化潜力，作为研究DS对血细胞发育和疾病影响的另一种手段。我们的具体目标是：1) 生成和表征来自患有和不患有唐氏综合症的个体的三体和整倍体 iPSC，2) 比较未分化 DS 和野生型 iPSC 以及源自这些 iPSC 组的造血祖细胞中 microRNA 和 mRNA 的表达和 3) 表征 DS 与整倍体 iPSC 的表观基因组。我们的长期目标是确定我们在 21 三体细胞中检测到的哪些 microRNA、mRNA 或甲基化差异导致 DS 中的异常造血。公共健康相关性：本研究与多种人类疾病相关：1）DS 儿童的短暂性骨髓增殖性疾病，2）DS 儿童的急性白血病，3）人类 DS 的多种非造血表型。对于唐氏综合症等复杂的遗传疾病，包括使用人类 iPSC 在内的强大新方法对于提高我们对该疾病分子基础的理解以及发现缓解该疾病症状的新方法绝对至关重要。