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。唐氏综合症是最常见的精神发育迟滞的原因，已知与染色体异常有关。它是由21号染色体的完全或部分三体（三重状态）引起的。唐氏综合症患者有不同程度的智力迟钝，以及其他几十种表型异常。目前尚不清楚21号染色体的三体性如何导致神经或其他病理表型。具体目标如下：[1]相对于整倍体对照，用21三体死后大脑、小脑和心脏样品进行基因表达谱分析。这些研究的目的是检验这一假设，即在分配给21号染色体的基因中存在基因表达的全局上调。通过基因表达谱分析和随后的确认研究，我们将确定在21三体组织中差异调节的特定基因。[2]确定唐氏综合征患者和整倍体对照的淋巴母细胞系的转录谱。这些患者已被临床表征（例如，通过神经行为评估和脑成像），并被分类为患有重度或轻度形式的唐氏综合征。我们将检验临床表型的严重程度与基因表达变化幅度相关的假设。[3]虽然前两个目标解决转录的变化，在这个目标中，我们测试的假设，翻译调节唐氏综合征。我们将对胎儿大脑和心脏以及淋巴母细胞进行定量免疫印迹。[4]我们在唐氏综合征中研究的机制可能与其他非整倍体有关。我们将确定冷冻脑和淋巴母细胞的转录谱与三体13（Patau综合征）和三体18（爱德华兹综合征）的个人。这些是与生命相容的其他主要三体。我们将检验这一假设，即在来自这些个体的细胞中，分别分配给13号和18号染色体的基因的表达存在全局上调。

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.