Regulation of the Human a7 Nicotinic Receptor Gene in Schizophrenia

人类 a7 烟碱受体基因在精神分裂症中的调控

• 批准号: 7612655
• 负责人: SHERRY LEONARD
• 金额: $ 27.72万
• 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: 2007-06-14 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612655
• 关键词: Accounting; Autopsy; Binding; Biochemical; Brain; Candidate Disease Gene; Cell Line; Chronic; Cognition; Cognitive; Complementary DNA; Country; Data; Defect; Disease; Enhancers; Etiology; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Human; In Vitro; Investigation; Laboratories; Mental disorders; Messenger RNA; Methodology; Mutation; Nicotine; Nicotinic Receptors; Nuclear; Nucleic Acid Regulatory Sequences; Patients; Plasmids; Polyribosomes; Population; Prevalence; Proteins; RNA Splicing; Receptor Gene; Regulation; Research; Running; Schizophrenia; Self Medication; Sensory; Site; Smoker; Smoking; Surface; Testing; Tobacco; Translations; Variant; Work; drug development; genetic linkage; mind control; non-smoker; promoter; receptor; receptor binding; research study; smoking prevalence; trafficking

DESCRIPTION (provided by PI): Schizophrenia is a chronic and debilitating mental illness with a prevalence of approximately 1%. A number of candidate genes are presently being investigated, although none has been definitively connected to the etiology of the disorder. Genetic linkage and biochemical studies support the investigation of the a7 nicotinic acetylcholine receptor gene (CHRNA7) as one of these candidate genes. The a7 gene has been designated by the MATRICS study group as an important receptor for development of drugs for cognition in schizophrenia. The a7* receptor is the target of nicotine in tobacco, a product used excessively in the schizophrenic population. Although smoking has declined in this country over the last twenty years, it has not decreased in in schizophrenics where >80% are heavy smokers. The a7 nicotinic receptor (a7*) has been implicated in cognitive and sensory deficits in schizophrenia, making regulation of this gene an important research problem for drug development. Surface expression of the a7* receptor, is decreased in postmortem brain of schizophrenic patients. Recent data from our laboratory shows that mRNA and protein levels for CHRNA7 are low in schizophrenic non-smokers, but brought to control levels or normalized in schizophrenic smokers, suggesting a defect in either transcription or translation. As the surface binding for this receptor is low in schizophrenic postmortem brain, the findings also suggest that assembly and trafficking of the receptor may be aberrant. This proposal will investigate three possible mechanisms for regulation of expression of the CHRNA7 gene in control and schizophrenic smokers and non-smokers (4 groups): 1) comparison of transcription of the gene. 2) comparison of translation, and 3) comparison of receptor assembly. Our hypothesis is that at one or more of these steps, there is a deficit in gene regulation of the CHRNA7 gene in schizophrenic subjects. The completion of this work will determine whether the hypothesized mechanisms are operative, contributing to the low levels of surface binding seen in postmortem brain of schizophrenic subjects. Lay statement: Schizophrenia is a chronic and debilitating illness with a strong genetic component. Several candidate genes are being studied, including the a7 nicotinic acetylcholine receptor, which responds to smoking. The prevalence of smoking in schizophrenia is very high, suggesting a form of self-medication. This proposal will investigate the regulation of the a7 nicotinic receptor gene in postmortem brain of control and schizophrenic smokers and non-smokers.

描述（PI提供）：精神分裂症是一种长期衰弱的精神疾病，患病率约为1％。 目前正在研究许多候选基因，尽管没有一个与该疾病的病因相关。 遗传连锁和生化研究支持A7烟碱乙酰胆碱受体基因（CHRNA7）作为这些候选基因之一的研究。 Matrics研究组已将A7基因指定为精神分裂症认知药物的重要受体。 A7*受体是烟草中尼古丁的靶标，烟草是精神分裂症人群中过度使用的产品。 尽管在过去的二十年中，该国的吸烟在该国有所减少，但在> 80％的吸烟者中，精神分裂症患者的吸烟量并未减少。 A7烟碱受体（A7*）与精神分裂症的认知和感觉缺陷有关，使该基因的调节成为药物开发的重要研究问题。 精神分裂症患者的死后大脑中A7*受体的表面表达降低。 我们实验室的最新数据表明，精神分裂症非吸烟者中CHRNA7的mRNA和蛋白质水平较低，但在精神分裂症患者中达到了控制水平或标准化，这表明转录或翻译中存在缺陷。 由于该受体的表面结合在精神分裂症后大脑中很低，因此发现还表明受体的组装和运输可能异常。 该建议将研究对照和精神分裂症的人和非吸烟者中CHRNA7基因表达表达的三种可能机制（4组）：1）基因转录的比较。 2）翻译的比较和3）受体组件的比较。 我们的假设是，从一个或多个步骤中，精神分裂症受试者的ChRNA7基因的基因调节存在不足。 这项工作的完成将确定假设的机制是否具有操作，从而导致精神分裂症患者死后大脑中看到的表面结合的低水平。 外行陈述：精神分裂症是一种具有强大遗传成分的慢性疾病。 正在研究几种候选基因，包括对吸烟反应的A7烟碱乙酰胆碱受体。 精神分裂症中吸烟的患病率很高，这表明一种自我治疗形式。 该提案将调查对照和精神分裂症患者和非吸烟者的死后大脑中A7烟碱受体基因的调节。