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: 7301548
• 负责人: SHERRY LEONARD
• 金额: $ 27.23万
• 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/7301548
• 关键词: Accounting; Autopsy; Binding; Biochemical; Brain; Candidate Disease Gene; Cell Line; Chronic; Cognition; Cognitive; Complementary DNA; Country; Data; Defect; 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; Numbers; 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（由 PI 提供）：精神分裂症是一种慢性且使人衰弱的精神疾病，患病率约为 1%。 目前正在研究许多候选基因，但没有一个基因与该疾病的病因学明确相关。 遗传连锁和生化研究支持对 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。 a7基因已被MATRICS研究小组指定为开发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，而烟草是一种在精神分裂症患者中过度使用的产品。 尽管过去二十年来这个国家的吸烟率有所下降，但精神分裂症患者的吸烟率并未下降，其中超过 80% 是重度吸烟者。 a7 烟碱受体 (a7*) 与精神分裂症的认知和感觉缺陷有关，因此对该基因的调控成为药物开发的重要研究问题。 精神分裂症患者死后大脑中 a7* 受体的表面表达降低。 我们实验室的最新数据表明，CHRNA7 的 mRNA 和蛋白质水平在精神分裂症非吸烟者中较低，但在精神分裂症吸烟者中达到控制水平或正常化，表明转录或翻译存在缺陷。 由于该受体的表面结合在精神分裂症患者死后大脑中较低，因此研究结果还表明该受体的组装和运输可能是异常的。 该提案将研究对照、精神分裂症吸烟者和非吸烟者（4 组）中 CHRNA7 基因表达调节的三种可能机制：1）基因转录的比较。 2) 翻译比较，3) 受体组装比较。 我们的假设是，在这些步骤中的一个或多个步骤中，精神分裂症受试者的 CHRNA7 基因的基因调控存在缺陷。 这项工作的完成将确定假设的机制是否有效，从而导致精神分裂症受试者死后大脑中表面结合水平较低。 外行陈述：精神分裂症是一种慢性、使人衰弱的疾病，具有很强的遗传因素。 一些候选基因正在研究中，包括对吸烟有反应的a7烟碱乙酰胆碱受体。 精神分裂症患者吸烟的患病率非常高，这表明吸烟是一种自我治疗的形式。 该提案将研究对照组、精神分裂症吸烟者和非吸烟者死后大脑中 a7 烟碱受体基因的调节情况。