GENE EXPRESSION AND GENETIC MENTAL RETARDATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项拟议的项目将调查患有遗传性MR的男孩样本以及一组患有未知但可能的遗传来源(UMR)的严重MR的基因表达模式和相关的分子事件。我们主要打算确定与MR相关的主要遗传病的基因表达谱，特别是唐氏综合征(DS)、脆性X综合征(FRAX)和非综合征X连锁MR(XLMR)和UMR。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，这些通路最终可能成为诊断和治疗目的的靶点。此外，通过初步的分子-表型相关性，我们打算对UMR的受试者进行分类，并确定sb正常表达的基因对所研究的MR组某些表型方面(变异)的具体贡献。将使用微阵列和免疫印迹分析来研究外周淋巴细胞和淋巴母细胞系的分子图谱，以进行组蛋白翻译后修饰。表型特征将包括详细的家族和临床病史、体检和全面的神经行为评估。该研究计划招募20名男性受试者，年龄5-10岁，患有重度MR(FSIQ：20-50)，分别来自DS、FRAX、XLMR和UMR组，并在12-18个月期间招募20名年龄/性别匹配的正常对照组。对分子图谱的分析将包括定制设计的数据库和生物信息学方法，将在整个为期两年的研究期间进行。我们推测，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，他们的表型的严重性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.