GENE EXPRESSION AND GENETIC MENTAL RETARDATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。拟议的项目将调查基因表达的模式，以及相关的分子事件，在一个样本的男孩与遗传性MR，以及在一组严重MR的未知，但可能的，遗传起源（UMR）。我们主要目的是鉴定与MR相关的两种主要遗传性疾病（特别是唐氏综合征（DS）、脆性X综合征（FraX）和非综合征混合型X连锁MR（XLMR））和UMR共同的基因表达谱。我们假设这些模式将包括连接突触活动和神经元基因表达的关键信号通路的异常，并且这些通路最终可以用于诊断和治疗目的。此外，通过初步的分子-表型相关性，我们打算对UMR受试者进行分类，并确定异常表达基因对研究中MR组表型某些方面的特定贡献（方差）。将使用微阵列和免疫印迹法对外周淋巴细胞和淋巴母细胞样细胞系的组蛋白翻译后修饰进行分子谱研究。表型特征将包括详细的家族史和临床史、体格检查和全面的神经行为评估。该方案计划在12 - 18个月期间从DS、FraX、XLMR和UMR组各招募20例5-10岁重度MR（FSIQ：20-50）男性受试者，以及20例年龄/性别匹配的正常对照。在为期两年的研究期间，将对分子模式进行分析，其中包括定制设计的数据库和生物信息学方法。我们假设这项研究将证明UMR患者与DS、FraX和XLMR患者在信号转导方面存在共同的异常，并且其表型的严重程度和其他方面可能与特定的基因和全局组蛋白修饰模式有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed project will investigate the patterns of gene expression, and associated molecular events, in a sample of boys with genetic MR as well as in a group of subjects with severe MR of unknown, but likely, genetic origin (UMR). We primarily intend to identify profiles of gene expression that are common to both major genetic disorders associated with MR, specifically Down syndrome (DS), Fragile X syndrome (FraX), and non-syndromix X-linked MR (XLMR), and UMR. We hypothesize that these patterns will include abnormalities in key signaling pathways that link synaptic activity and neuronal gene expression, and that these pathways could eventually be targeted for diagnostic and therapeutic purposes. In addition, by preliminary molecular-phenotypical correlations, we intend to both classify subjects with UMR and determine the specific contributions of sbnormally-expressed genes to (the variance) of certain aspects of the phenotype of the MR groups under study. Molecular profiles will be studied on peripheral lymphocytes and lymphoblastoid cell lines using microarray and immunoblotting assays for histone posttranslational modifications. Phenotypical characterizations will include detailed family and clinical history, physical examination, and comprehensive neurobehavioral evaluation. The protcol intends to recruit 20 male subjects, ages 5-10 years, with severe MR (FSIQ: 20-50) from each DS, FraX, XLMR, and UMR groups, and 20 age/sex matched normal controls, over a 12 -18 month period. Analyses of molecular pateerns, which will include custom-designed databases and bioinformatics approaches, will be conducted throughout the two-year study period. We postulate that this study will demonstrate that patients with UMR share abnormalities in signal transduction with subjects with DS, FraX, and XLMR and that the severity and otehr aspects of their phenotype can be linked to specific genes and patterns of global histone modifications.