REGULATION OF CHRNA7 EXPRESSION

CHRNA7表达的调控

• 批准号: 7752182
• 负责人: ROBERT R FREEDMAN
• 金额: $ 25.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752182
• 关键词: 3' Untranslated Regions; Adult; Affect; Agonist; Amino Acids; Animal Model; Auditory; Autopsy; Basic Science; Biological Assay; Brain; Cell membrane; Choline; Clinical; DBA/2 Mouse; DNA-Protein Interaction; Development; Electrophoretic Mobility Shift Assay; Ethnic group; Family; Functional disorder; Gene Deletion; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Heterogeneity; Hippocampus (Brain); Human; Impaired cognition; Individual; Infant Development; Instruction; Intervention; Investigation; Link; Luciferases; Microarray Analysis; Molecular Biology; Molecular Neurobiology; Mus; Mutation; NRG1 gene; National Institute of Mental Health; Neuregulins; Neurons; Nicotinic Receptors; Nucleic Acid Regulatory Sequences; Nutrient; Perinatal; Persons; Pharmaceutical Preparations; Pharmacogenetics; Preventive Intervention; Principal Investigator; Psychotic Disorders; Regulation; Reporter; Research Personnel; Research Support; Risk; Schizophrenia; Screening procedure; Symptoms; Transgenic Mice; Treatment outcome; analog; base; design; drug development; endophenotype; experience; genetic analysis; genetic linkage; improved; in vitro Assay; infancy; mouse model; new therapeutic target; novel therapeutics; prevent; promoter; protein structure; sensory gating; transmission process

Project 3 identified CHRNA7 as the gene that is linked to the PSO sensory gating abnormality in schizophrenia and found functional SNPs in the core promoter of the gene that are associated with this abnormality. Genetic linkage to 15q13.3, the locus of CHRNA7 has been found in multiple ethnic groups, and recent evidence suggests that rare deletions of the gene are associated with schizophrenia. The human molecular biology studies in this Project characterize mutation, function, and regulation of CHRNA7. To fulfill the need for clinically useful genomics, the human molecular biology project has undertaken extensive screening of CHRNA7 to find its pathogenic mutations. A critical finding is that the amino acid structure of the protein is generally normal in schizophrenia and thus most abnormalities involve regulation of its expression. Project 1 has used that information to design a new therapeutic. Project 3 will continue to support drug development by identifying new polymorphisms, one of which already shows preliminary evidence of a pharmacogenetic effect. Investigation of the 5' and 3' regulatory regions in Aim 1 interacts with similar efforts of Project 4 in DBA/2 mice, which also have CHRNA7 mutations. Functional mutations in human CHRNA7 \N'\\\ be introduced into transgenic mouse models in Project 5. Genotypes may eventually identify individuals who are likely to have genetically determined pathobiology involving a7nAChRs. Project 2's preventive intervention in infancy similarly requires information about CHRNA7 and other genes that convey risk for schizophrenia such as NRG1, a gene associated with risk for schizophrenia that is involved in the developmental expression of aTnAChRs. Aim 2 will determine how NRG1 and CHRNA7 polymorphisms both act to increase risk for schizophrenia. Psychiatric molecular biology in the Center includes more than genomics. Project 2 is now involved in perinatal treatment with choline as an a7nAchR agonist. In Aim 3, Project 3 will contribute its microarray technology to characterize the changes in gene expression that result in animal models from Projects 4-6 that receive this treatment. Results will be compared with our previous experience in characterizing gene expression in postmortem brain from persons who had schizophrenia. Project 3 provides basic research support to Projects 1 and 2 and interacts with basic researchers in Proiects 4, 5, and 6. It receives statistical qenetics support from Core B. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this ri^r.e^riirsr

项目3将CHRNA7识别为与PSO感觉门控异常有关的基因 精神分裂症并在基因的核心启动子中发现与此相关的功能性SNP 紊乱 etc。遗传与15q13.3的遗传联系，在多个族裔中发现了CHRNA7的基因座，并且 最近的证据表明，该基因的罕见缺失与精神分裂症有关。人类 该项目的分子生物学研究表征了CHRNA7的突变，功能和调节。实现 需要临床上有用的基因组学，人类分子生物学项目已进行了广泛的研究 筛选CHRNA7以找到其致病突变。一个关键的发现是 该蛋白在精神分裂症中通常是正常的，因此大多数异常涉及调节其 表达。项目1使用该信息设计了一种新的治疗性。项目3将继续 通过识别新的多态性来支持药物开发，其中之一已经显示 药物遗传学作用的证据。 AIM 1相互作用中5'和3'监管区域的调查 在DBA/2小鼠中，项目4的类似努力，也具有CHRNA7突变。功能突变 在项目5中将人类chrna7 \ n'\\\引入转基因小鼠模型中。基因型最终可能 识别可能具有涉及A7NACHR的遗传学病原体学的个体。 项目2的婴儿预防性干预类似地需要有关CHRNA7和其他的信息 传达精神分裂症的风险（例如NRG1）的基因，NRG1是一种与精神分裂症风险相关的基因 参与ATNACHRS的发展表达。 AIM 2将确定NRG1和CHRNA7的方式 多态性都起作用，以增加精神分裂症的风险。 该中心的精神病分子生物学包括基因组学的更多。项目2现在参与 胆碱作为A7NACHR激动剂的围产期治疗。在AIM 3中，项目3将贡献其微阵列 表征基因表达变化的技术，导致项目4-6的动物模型 得到这种治疗。结果将与我们以前在表征基因的经验进行比较 患有精神分裂症患者的死后大脑中的表达。 项目3为项目1和2提供基础研究支持，并与基础研究人员互动 Proiects 4、5和6。 相关性（请参阅说明）： 需要针对精神分裂症的新治疗策略来改善认知功能障碍和阴性 症状并防止精神病的发展。该中心研究了烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计一种新药物治疗 精神分裂症和婴儿发育过程中的预防养分干预措施，这两者都激活了这一点 ri^r.e^riirsr