REGULATION OF CHRNA7 EXPRESSION

项目3确定CHRNA7是与PSO感觉门控异常相关的基因 并在该基因的核心启动子中发现了与此相关的功能性SNP 反常现象。与15q13.3的遗传连锁，在多个民族中发现了CHRNA7基因座，并 最近的证据表明，该基因罕见的缺失与精神分裂症有关。人类 本项目中的分子生物学研究描述了CHRNA7的突变、功能和调控。履行 由于需要临床上有用的基因组学，人类分子生物学计划已经进行了广泛的 筛选CHRNA7基因，寻找其致病突变。一个重要的发现是，氨基酸结构 该蛋白在精神分裂症患者中通常是正常的，因此大多数异常涉及其调节 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 通过识别新的多态来支持药物开发，其中一个已经显示出初步的 药物遗传效应的证据。AIM 1相互作用中5‘和3’调控区的研究 在同样存在CHRNA7突变的DBA/2小鼠身上，与Project 4的作用类似。基因的功能突变 在项目5中将人CHRNA7\N‘\引入转基因小鼠模型。 确定可能具有涉及A7nAChRs的基因决定的病理生物学的个体。 项目2：S婴儿期预防干预同样需要了解CHRNA7和其他 传递精神分裂症风险的基因，如NRG1，一种与精神分裂症风险相关的基因 参与aTnAChRs的发育表达。目标2将确定NRG1和CHRNA7如何 基因多态都会增加患精神分裂症的风险。 该中心的精神病学分子生物学不仅包括基因组学。项目2现在参与了 用胆碱作为7nAchR激动剂的围产期治疗。在AIM 3中，项目3将贡献其微阵列 项目4-6中描述导致动物模型的基因表达变化的技术 接受这种治疗的人。结果将与我们以前在基因表征方面的经验进行比较 精神分裂症患者死后脑中的表达。 项目3为项目1和项目2提供基础研究支持，并与基础研究人员在 项目4、5和6。它从核心B获得统计遗传学支持。 相关性(请参阅说明)： 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 并能预防精神病的发展。该中心研究一种烟碱型乙酰胆碱 受体作为新的治疗靶点。研究结果被用来设计一种新的药物治疗方法 精神分裂症和婴儿发育期间的预防性营养干预，两者都激活了这一 Ri^r.e^riirsr

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