MOLECULAR BIOLOGY OF NICOTINIC RECEPTORS

烟碱受体的分子生物学

• 批准号: 7449573
• 负责人: SHERRY LEONARD
• 金额: $ 41.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449573
• 关键词: 15q14; Address; Affect; Autopsy; Biological; Brain; COMT gene; Candidate Disease Gene; Catechol O-Methyltransferase; Chromosomes; DNA; Development; Diagnosis; Disease; Evaluation; Functional Imaging; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Human; In Vitro; Life; Link; Measures; Messenger RNA; Microarray Analysis; Molecular Biology; Mutation; Neurobiology; Neurons; Nicotinic Receptors; Nucleic Acid Regulatory Sequences; Pathogenesis; Pharmaceutical Preparations; Phenotype; Promoter Regions; RNA Splicing; Receptor Gene; Research Personnel; Role; SNP genotyping; Schizophrenia; Site; TNFRSF5 gene; Variant; genetic pedigree; human subject; mind control; neurophysiology; proband; protein expression; receptor expression; response

The Center proposes four postulates for investigating the role of genetic polymorphism in the alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) in schizophrenia: (1) identification and association of polymorphisms in CHRNA7 with schizophrenia, (2) demonstration of a functional effect of the polymorphism expression at the cellular level, (3) relation of the polymorphisms to deficits in brain function associated with the illness, and (4) reversal of the deficits in brain function by treatment directed at the cellular dysfunction caused by CHRNA7. This Project will address Postulates 1 and 2 by providing for the Center Investigators, genotyping of DNA from both live subjects and from postmortem brain, and in vitro evaluation of association with diagnosis and with function. CHRNA7 has been selected as the most likely candidate gene in the chromosome 15q14 linkage region by multiple biological and genetic studies. Functional mutations, consistent with reduced expression of the gene, were found in the proximal promoter region of the CHRNA7 gene. These are associated with both schizophrenia and the P50 deficit in the disease. Additional regulatory regions have been found in the 5' upstream region of the gene that contain polymorphic sites. This Project, Aim 1 will complete genotyping in 5' upstream regulatory regions, sequence the remaining sections of the gene in 10 probands from linked pedigrees, and investigate an associated intronic variant that may affect RNA splicing. SNPs in the four other genes in this region will be examined as well. As suggested by the Reviewers, we will also provide SNP genotyping for another gene with functional mutations, COMT, for association with schizophrenia and the phenotypes being investigated in this and other projects. For Postulate 2, Aim 2 will investigate the association of CHRNA7 mutations with CHRNA7 mRNA and protein expression in human postmortem brain of control and schizophrenic subjects. In Aim 3, we will further investigate the effects of CHRNA7 associated and functional mutations on the expression of other genes, utilizing microarray technology. The consequences of mutations in CHRNA7 on expression of CHRNA7, itself, and of other genes may have pathophysiological importance for the projects in the Center.

该中心提出了四个假设，用于研究遗传多态性在α7神经元烟碱乙酰胆碱受体基因（CHRNA7）在精神分裂症中的作用：（1）Chrna7中多态性的多态性鉴定和关联，Chrna7与精神分裂症的表现，（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（3）与疾病相关的脑功能缺陷的多态性，以及（4）通过针对CHRNA7引起的细胞功能障碍的治疗来逆转脑功能缺陷。该项目将通过为中心研究人员，现场受试者和死后大脑的DNA进行基因分型来解决假设1和2，以及对诊断和功能关联的体外评估。 CHRNA7已通过多种生物学和遗传研究选择为15q14连锁区域中最有可能的候选基因。在ChRNA7基因的近端启动子区域中发现了与基因表达降低一致的功能突变。这些与疾病中的精神分裂症和P50不足有关。在包含多态位点的基因上游区域中发现了其他调节区域。该项目AIM 1将在5'上游调节区域中完成基因分型，并将基因的其余部分从连接的谱系中的10个概率分析中，并研究可能影响RNA剪接的相关内含子变体。该地区其他四个基因中的SNP将被检查为 出色地。正如审稿人所建议的那样，我们还将为另一个具有功能突变的基因提供SNP基因分型，以与精神分裂症相关，并在该项目和其他项目中研究了表型。对于假设2，AIM 2将研究CHRNA7突变与CHRNA7 mRNA和蛋白质在对照和精神分裂症受试者的死后大脑中的蛋白质的关联。在AIM 3中，我们将进一步研究CHRNA7相关和功能突变对使用微阵列技术的其他基因表达的影响。 CHRNA7突变对CHRNA7，本身和其他基因表达的后果可能对中心项目具有病理生理的重要性。