精神分裂症易感基因KCNH2和KCNH7通道活性的分子调控机制

精神分裂症(SCH)作为常见复杂疾病，遗传因素在其病理机制中起重要作用。文献及前期研究提示在大脑中表达的钾离子通道Kv11家族的KCNH2和KCNH7与SCH发病风险和/或抗精神病药物效显著相关。Kv11家族通道保守的PAS结构域缺失后，截短型的KCNH2-3.1失活变快，且通道活性更易受到利培酮抑制；本人的前期研究也显示KCNH7的单核苷酸多态性与利培酮药物疗效显著相关。本研究拟在前期基础上，进一步阐释KCNH2、KCNH7的分子调控机制：首先通过酵母双杂交及CoIP实验筛选与通道互作的蛋白；其后，借助电生理检测明确互作蛋白对通道活性的影响；之后，利用动物模型验证互作蛋白对认知行为的影响。最后，应用药理学实验和临床药理学数据关联分析，进一步确定通道的调控蛋白与SCH药效及药物靶点的关联。预期结果有望解析KCNH2和KCNH7在大脑中的分子调控机制，为阐释SCH病理机制及研发新药提供依据。

Schizophrenia (SCH) is a common severe psychiatric disorder, and the genetic factors play a major role in its pathogenesis. Previous studies have revealed that KCNH2 and KCNH7, which belongs to Kv11 family and expressed in the brain, are significantly associated with the risk of SCH and/or antipsychotic drug efficacy. The truncated isoform KCNH2-3.1, which absent the conserved PAS domain of Kv11 family, showed faster deactivation and its channel activity was more easily blocked by risperidone. KCNH7 polymorphisms showed significant association with risperidone treatment responses in our previous pharmacogenetics study. This research intends to explore the molecular regulation mechanisms of KCNH2 and KCNH7 on the basis of the previous studies. Firstly, the proteins interacting with channels will be screened by yeast two-hybrid and CoIP assay. Then, the impact of interacting protein to channel activity of KCNH2 and KCNH7 will be verified by electrophysiological experiments. After that, animal models will be used to verify the effects of interacting proteins on cognitive behavior. Finally, pharmacological experiments and clinical pharmacological data analyses will be applied to further determine the association between the regulatory protein of channels and the drug efficacy and target discovery of SCH. The above research will not only reveal the molecular regulation mechanism of the interacting proteins of KCNH2 and KCNH7 in brain, but also contribute to the pathogenesis of schizophrenia and the development of new antipsychotics.