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CHRNA 7鉴定为与PSO感觉门控异常相关的基因， 精神分裂症，并在与此相关的基因的核心启动子中发现了功能性SNP。 异常与CHRNA 7基因座15q13.3的遗传连锁已在多个种族群体中发现， 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 本项目的分子生物学研究描述了CHRNA 7的突变、功能和调节。履行 为了满足临床上有用的基因组学的需要，人类分子生物学项目已经进行了广泛的研究， 筛选CHRNA 7以发现其致病性突变。一个关键的发现是， 该蛋白质在精神分裂症中通常是正常，因此大多数异常涉及其 表情项目1利用这些信息设计了一种新的治疗方法。项目3将继续 通过识别新的多态性来支持药物开发，其中一种已经初步显示出 药物遗传学效应的证据。Aim 1相互作用中5'和3'调节区的研究 与项目4在DBA/2小鼠中的类似努力，DBA/2小鼠也具有CHRNA 7突变。功能突变 在项目5中，将人CHRNA 7引入转基因小鼠模型中。基因型最终可能 鉴定可能具有涉及α 7 nAChR的遗传决定的病理生物学的个体。 项目2在婴儿期的预防性干预同样需要关于CHRNA 7和其他基因的信息。 与精神分裂症风险相关的基因，如NRG 1， 参与aTnAChRs的发育表达。目标2将确定NRG 1和CHRNA 7 多态性都增加了患精神分裂症的风险。 该中心的精神病学分子生物学包括基因组学。项目2目前正在参与 胆碱作为α 7 nAchR激动剂的围产期治疗。在目标3中，项目3将贡献其微阵列 描述导致项目4-6动物模型的基因表达变化的技术 接受这种治疗。结果将与我们以前的经验进行比较，在表征基因 在精神分裂症患者死后大脑中的表达。 项目3为项目1和项目2提供基础研究支持，并与 项目4、5和6。它从Core B获得统计学支持。 相关性（参见说明）： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 症状并预防精神病的发展。该中心研究了一种烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计一种新的药物治疗， 精神分裂症和婴儿发育期间的预防性营养干预，这两者都激活了这一点。 里里尔河