Regulation of Gene Expression in Down Syndrome

描述（由申请人提供）：拟议研究的广泛，长期目标是确定21三体（唐氏综合征）对转录（基因表达）和翻译的影响。唐氏综合症是已知与染色体异常有关的智力迟钝最常见的原因。它是由21号染色体的完全或部分三体（三复制状态）引起的。唐氏综合症患者有不同程度的智力迟钝，以及数十种其他表型异常。目前尚不清楚21号染色体三体是如何引起神经或其他病理表型的。具体目的如下：[1]与整倍体对照进行21三体死后大脑、小脑和心脏样本的基因表达谱分析。这些研究的目的是验证一个假设，即在21号染色体上的基因中存在一个全局的基因表达上调。通过基因表达谱和随后的确认研究，我们将确定在21三体组织中差异调节的特定基因。测定唐氏综合征患者和整倍体对照淋巴母细胞系的转录谱。这些患者具有临床特征（例如，神经行为评估和脑成像），并被分为严重或轻度唐氏综合征。我们将检验临床表型的严重程度与基因表达变化的大小相关的假设。虽然前两个目的是解决转录变化，但在这个目的中，我们检验了翻译在唐氏综合症中受到调节的假设。我们将对胎儿的大脑和心脏以及淋巴细胞进行定量免疫印迹。我们在唐氏综合症中研究的机制可能与其他非整倍体有关。我们将确定13三体（Patau综合征）和18三体（Edwards综合征）患者的冷冻脑和淋巴细胞的转录谱。这些是与生命相容的其他主要三体。我们将验证这一假设，即在来自这些个体的细胞中，分别分配给13号染色体和18号染色体的基因表达存在全局上调。

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to define the consequence of trisomy 21 (Down syndrome) on transcription (gene expression) and translation. Down syndrome is the most frequently occurring cause of mental retardation known to be associated with a chromosomal abnormality. It is caused by a complete or partial trisomy (triplicate state) of chromosome 21. Individuals with Down syndrome have mental retardation to varying degrees, as well as dozens of other phenotypic abnormalities. It is not known how the trisomy of chromosome 21 causes neurological or other pathological phenotypes. The specific aims are as follows: [1] Perform gene expression profiling with trisomy 21 postmortem cerebrum, cerebellum, and heart samples relative to euploid controls. The purpose of these studies is to test the hypothesis that there is a global up-regulation of gene expression in genes assigned to chromosome 21. Through gene expression profiling and subsequent confirmation studies, we will define specific genes that are differentially regulated in trisomy 21 tissues. [2] Determine the transcriptional profile in lymphoblast cell lines from Down syndrome patients and euploid controls. These patients have been clinically characterized (e.g. with neurobehavioral evaluations and brain imaging) and are classified as having severe or mild forms of Down syndrome. We will test the hypothesis that the severity of the clinical phenotype correlates to the magnitude of gene expression changes. [3] While the first two aims address transcriptional changes, in this aim we test the hypothesis that translation is regulated in Down syndrome. We will perform quantitative immunoblotting of fetal brain and heart as well as lymphoblasts. [4] The mechanisms we study in Down syndrome may be relevant to other aneuploidies. We will determine the transcriptional profile in frozen brain and lymphoblasts from individuals with trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome). These are the other major trisomies compatible with life. We will test the hypothesis that in cells derived from these individuals there is a global up-regulation of the expression of genes assigned to chromosomes 13 and 18, respectively.