Regulation of the Human a7 Nicotinic Receptor Gene in Schizophrenia

描述（由PI提供）：精神分裂症是一种慢性衰弱性精神疾病，患病率约为1%。目前正在研究一些候选基因，尽管没有一个与该疾病的病因有明确的联系。遗传连锁和生化研究支持了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matrix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，而烟草是精神分裂症患者过度使用的一种产品。尽管在过去的二十年里，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没有下降，其中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，使该基因的调控成为药物开发的一个重要研究问题。精神分裂症患者死后脑a7*受体表面表达降低。我们实验室最近的数据显示，非吸烟者的精神分裂症患者的CHRNA7 mRNA和蛋白水平较低，而吸烟者的CHRNA7 mRNA和蛋白水平处于控制水平或正常水平，这表明其转录或翻译存在缺陷。由于这种受体的表面结合在精神分裂症患者死后的大脑中很低，研究结果还表明，受体的组装和运输可能是异常的。本研究拟探讨三种可能的CHRNA7基因在对照和精神分裂症吸烟者和非吸烟者（4组）中的表达调控机制：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，有助于在精神分裂症受试者死后的大脑中观察到低水平的表面结合。Lay statement：精神分裂症是一种慢性衰弱性疾病，有很强的遗传成分。几个候选基因正在研究中，包括a7烟碱乙酰胆碱受体，它对吸烟有反应。精神分裂症患者中吸烟的患病率非常高，这表明有一种自我药物治疗的形式。本研究将探讨a7烟碱受体基因在对照、精神分裂症吸烟者和非吸烟者死后大脑中的调控作用。

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.