Identification of functional nAChR variants and their role in nicotine addiction, schizophrenia and epilepsy

功能性 nAChR 变异的鉴定及其在尼古丁成瘾、精神分裂症和癫痫中的作用

• 批准号: 24391301
• 负责人: Professor Dr. Daniel Bertrand
• 金额: --
• 依托单位: Département des Neurosciences Fondamentales
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/24391301?language=en
• 关键词: Identification; functional; nAChR; variants; their

Genetic variants are a common finding in our genes, but most variants are functionally silent (non-functional variants). The rare functional variants can more or less subtly change the way the proteins encoded by those genes are working. Phenotypically they can, for example, alter our individual responses to drugs or our susceptibility for certain disorders. It is likely that functional gene variants also determine our liability for substance dependence. Functional variants in genes for neuronal nicotinic acetylcholine receptors (nAChRs) can be regarded as prime candidates if one is looking for genetic factors in nicotine dependence. The major aim of the present proposal is the identification of nAChR variants that influence the development of nicotine dependence, the severity of the addiction and the chances of successful and long-term smoking cessation. Our project will include the systematic search for functional nAChR variants as well as their analysis in patients. For the first part, the promoters, coding and intronic regions and 375 - untranslated regions of nAChR genes will be sequenced and the obtained variants introduced into expression clones. The clones will be expressed in different cell types and their biopharmacological profiles analysed in detail. In close cooperation with other groups in the Schwerpunkt genetic variants that prove to be functional will subsequently be studied in large samples of patients with different endophenotypes of nicotine dependence as well as in schizophrenic patients. The association approach aims to identify variants that prove to be more frequent in patients than in controls and are therefore likely to play a causal role in nicotine dependence.

遗传变异在我们的基因中是一种常见的发现，但大多数变异是功能沉默的（非功能变异）。这些罕见的功能变异或多或少会微妙地改变由这些基因编码的蛋白质的工作方式。例如，从表型上看，它们可以改变我们对药物的个体反应或对某些疾病的易感性。很可能功能性基因变异也决定了我们对物质依赖的倾向。神经尼古丁乙酰胆碱受体（nAChRs）基因的功能变异可以被认为是尼古丁依赖遗传因素的主要候选者。本提案的主要目的是确定影响尼古丁依赖发展、成瘾严重程度以及成功和长期戒烟机会的nAChR变异。我们的项目将包括对功能性nAChR变异的系统搜索以及对患者的分析。第一部分将对nAChR基因的启动子、编码区和内含子区以及375 -非翻译区进行测序，并将获得的变异引入表达克隆。克隆将在不同的细胞类型中表达，并详细分析其生物药理学特征。在与Schwerpunkt基因变异的其他研究小组的密切合作下，证明具有功能的基因变异将随后在具有不同尼古丁依赖内表型的患者以及精神分裂症患者的大量样本中进行研究。关联方法的目的是找出在患者中比在对照组中更常见的变异，因此可能在尼古丁依赖中起因果作用。