Epigenetic Modifiers in Down Syndrome

唐氏综合症的表观遗传修饰剂

基本信息

批准号：
7976426
负责人：
Benjamin Tycko
金额：
$ 27.79万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7976426
关键词：
Adult Affect Age Aged, 80 and over Anemia Aneuploidy Area Autoimmune Diseases Autoimmunity Biological Assay Biology Blood Cells Brain Candidate Disease Gene Caring Cell Culture Techniques Cell physiology Childhood Leukemia Chromosomes Chromosomes, Human, Pair 21 Collection Congenital Heart Defects Congenital chromosomal disease DNA DNA Methylation Data Data Analyses Dementia Development Down Syndrome Employee Strikes Epigenetic Process Future Genes Genetic Genomics Individual Individual Differences Infection Intellectual functioning disability Knock-out Leukocytes Medical Methods Methylation Organ Pathogenesis Pattern Peripheral Blood Mononuclear Cell Phenotype Predisposition Recurrence SNP genotyping Sampling Severities Site Survivors Syndrome Testing Tissues Transgenic Mice Translating Triage Update Variant Work age related bisulfite clinical phenotype cognitive function cohort indexing insight mRNA Expression mouse model neutrophil peripheral blood research study response

项目摘要

A striking feature of Down syndrome (DS; trisomy 21; +21) is the wide range of severity, with strong inter-individual differences in its major features. These include cardiac defects, baseline cognitive function and age-related dementia, as well as several important phenotypes due to altered development and function of blood cells (e.g., childhood leukemias, anemia, autoimmune disorders, and susceptibility to infections). In most cases the genetic or epigenetic factors underlying this variation, and indeed the pathogenesis of the phenotypes themselves, remain largely unknown. Here we hypothesize that the relevant tissues in people with +21 may have accumulated altered patterns of DNA methylation on chromosome 21 and on other chromosomes, potentially affecting some or all of these phenotypes. We have substantial preliminary data supporting this hypothesis, from a profiling method that we developed called MSNP, and from a complementary platform, lllumina Infinium assays. In this highly interactive project we will carry out MSNP and lllumina Infinium assays on peripheral blood leukocyte (PBL) DNAs from people with DS spanning a wide range of ages, including a unique collection of the oldest old survivors, comparing the results with normal controls spanning the same age range. We will validate this epigenetic analysis with bisulfite Pyrosequencing, and correlate the methylation indices and SNP genotypes at the loci with strongest differential methylation with the severity of anemia, autoimmune disorders, and recurrent infections in more than 400 adults with DS. In parallel, we will carry out direct functional studies of the highest priority differentially methylated genes using cell culture and mouse models. While this project is focused on blood cell-related phenotypes, the data may additionally provide a proof-of-principle for future studies of altered DNA methylation in other major organs, including the brain, in this important chromosomal disorder.

唐氏综合症（DS; Trisome 21; +21）的一个惊人特征是广泛的严重性，其主要特征具有很强的个体间差异。这些包括心脏缺陷，基线认知功能和与年龄相关的痴呆，以及由于血细胞的发育和功能改变和功能而引起的几种重要表型（例如，儿童白血病，贫血，自身免疫性疾病以及对感染的敏感性）。在大多数情况下，这种变异的遗传或表观遗传因素，实际上表型本身的发病机理仍然在很大程度上未知。在这里，我们假设+21患者的相关组织可能会积累在21染色体和其他染色体上的DNA甲基化模式改变，可能会影响某些或所有这些表型。我们有大量的初步数据支持这一假设，从我们开发的称为MSNP的分析方法以及互补的平台Lllumina Infinium Assays。在这个高度互动的项目中，我们将对来自多个年龄范围的DS人的外周血白细胞（PBL）DNA进行MSNP和Lllumina Infinium测定法，其中包括最古老的老年幸存者的独特集合，将结果与正常对照范围跨越同一年龄范围的结果进行了比较。我们将用硫酸硫酸硫酸苯甲异氨酸测序验证这种表观遗传分析，并将甲基化相关贫血，自身免疫性疾病的严重程度以及400多名DS成年人的疾病，自身免疫性疾病的严重程度和反复感染，该基因座的指标和SNP基因型具有最强的差分甲基化。同时，我们将使用细胞培养和小鼠模型对最高优先级差异甲基化基因进行直接功能研究。虽然该项目集中在与血细胞相关的表型上，但数据还可以为未来在包括大脑在内的其他主要器官（包括大脑）在这种重要的染色体疾病中改变DNA甲基化的未来研究提供原则证明。