Lymphocytic Targets and Behavior in Fragile X

描述（由申请人提供）：脆性X综合征（FraX）是遗传性精神发育迟滞的最常见形式，与FMRP（一种参与蛋白质合成调节的蛋白质）缺失相关。最近的微阵列研究已经确定了转录本，这些转录本在FMRP基因敲除小鼠的大脑和FraX男性的淋巴母细胞中都受到异常调节。这些FMRP靶标包括参与突触发育和可塑性的结构和功能蛋白。此外，使用蛋白质组学技术，我们已经证明在FraX淋巴细胞异常乙酰化的几种蛋白质，包括小胶质细胞调节蛋白膜联蛋白-1（Anx-1）和神经元细胞骨架蛋白α-微管蛋白。异常的Anx-1表达也是FraX自闭症特征的预测因子。我们假设FraX神经行为表型的特定方面（例如自闭症、巨脑畸形）和变异性是一种或多种神经蛋白异常表达的结果，并且这些贡献可以通过表征淋巴细胞中异常神经蛋白表达的模式及其在FraX男性中的神经行为相关性来鉴定。我们建议研究12个选定的FMRP目标在淋巴细胞中的表达模式，从一个特征良好的样本的男性与FraX，代表频谱的神经行为表型表现。在目的1中，我们将使用免疫化学技术的组合来表征100名患有FraX的男性和20名对照中淋巴细胞蛋白表达的模式和水平。在目标2中，我们将研究这些分子变量与神经行为表型的选择性方面之间的关系（例如，a-微管蛋白和IQ）。由于50名FraX受试者和10名对照受试者的血液样本和行为数据可用，因此两年内仅招募一半样本。初步数据还显示了研究4种拟议蛋白质的可行性。由于他们的创新方法来检查基因型-表型关系，我们相信，拟议的研究是根据探索/发展补助金（R21）计划的目的。

DESCRIPTION (provided by applicant): Fragile X syndrome (FraX), the most prevalent form of inherited mental retardation, is associated with the absence of FMRP, a protein involved in regulation of protein synthesis. Recent microarray studies have identified transcripts that are abnormally regulated in both brains from FMRP knockout mice and lymphoblasts from males with FraX. These FMRP targets include structural and functional proteins that participate in synaptic development and plasticity. In addition, using proteomics techniques, we have demonstrated in FraX lymphocytes abnormal acetylation of several proteins that include the microglial regulatory protein annexin-1 (Anx-1) and the neuronal cytoskeletal protein a-tubulin. Abnormal Anx-1 expression is also predictive of autistic features in FraX. We hypothesize that specific aspects (e.g, autism, megalencephaly), and variability, of the FraX neurobehavioral phenotype are the consequence of abnormal expression of one or more neural proteins, and that these contributions can be identified by characterizing patterns of abnormal neural protein expression in lymphocytes and their neurobehavioral correlates in males with FraX. We propose to study the patterns of expression of 12 selected FMRP targets in lymphocytes from a well-characterized sample of males with FraX, representing the spectrum of neurobehavioral phenotypic manifestations. In Aim l, we will use a combination of immunochemical techniques to characterize patterns and levels of lymphocytic protein expression in 100 males with FraX and 20 controls. In Aim 2, we will examine the relationships between these molecular variables and selective aspects of the neurobehavioral phenotype (e.g., a-tubulin and IQ) of the FraX subjects. Since blood samples and behavioral data are available on 50 FraX and 10 control subjects, only half of the sample will be recruited over two years. Preliminary data also show the feasibility of studying 4 of the proposed proteins. Because of their innovative approach to examining genotype-phenotype relationships, we believe that the proposed studies are in accordance with the purposes of the Exploratory/Developmental Grant (R21) Program.