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和衰弱性精神疾病，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明确相关。 遗传连锁和生化研究支持α 7烟碱乙酰胆碱受体基因（CHRNA 7）作为这些候选基因之一的调查。 MATRICS研究小组已将α 7基因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目标，烟草是精神分裂症患者过度使用的产品。 尽管在过去的20年里，吸烟在这个国家有所减少，但精神分裂症患者的吸烟率并没有减少，其中80%以上是重度吸烟者。 α 7烟碱受体（α 7 *）与精神分裂症的认知和感觉缺陷有关，这使得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脑中a7* 受体的表面表达减少。 我们实验室的最新数据显示，CHRNA 7的mRNA和蛋白质水平在不吸烟的精神分裂症患者中较低，但在吸烟的精神分裂症患者中达到控制水平或正常化，这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死后大脑中很低，研究结果还表明受体的组装和运输可能是异常的。 本研究将探讨对照组、精神分裂症吸烟者和非吸烟者（4组）中CHRNA 7基因表达调控的三种可能机制：1）比较该基因的转录。 2)翻译的比较; 3）受体组装的比较。 我们的假设是，在这些步骤中的一个或多个步骤中，精神分裂症受试者中CHRNA 7基因的基因调控存在缺陷。 这项工作的完成将确定是否假设的机制是可操作的，有助于在精神分裂症受试者死后大脑中看到的低水平的表面结合。 外行陈述：精神分裂症是一种具有强烈遗传成分的慢性和使人衰弱的疾病。 几个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。 吸烟在精神分裂症中的流行率非常高，这表明了一种自我治疗的形式。 本研究拟探讨吸烟者、非吸烟者及精神分裂症患者死后脑组织中α 7烟碱受体基因的调控。

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.