躁郁症是一种常见的遗传性精神疾患，其发病机理仍然未知且是目前国际上的前沿课题。我们以往的研究率先在分子和细胞水平证明躁郁症与生物钟有关。通过基因芯片我们发现Nov基因受生物钟控制且呈周期性表达，其表达水平在脑组织尤其是视交叉上核（中枢生物钟）为最高，且Nov基因位于躁郁症疑似染色体位点，据此我们确定Nov为躁郁症候选基因。本项目通过建立脑组织缺陷小鼠模型来研究Nov基因对生物钟及精神状态的影响。来源于Nov缺失小鼠的脑组织和外周组织切片及分离的神经和外周细胞将用实时荧光记录方法检测生物钟的变化，转轮实验及Open Field、Plus Maze、Forced Swim等实验将用于测定Nov缺失在整体水平对生物钟及精神状态的影响，体外表达的Nov蛋白及治疗或诱导躁郁症的药物将被用于以上实验以验证Nov在生物钟调控及躁郁症发病机理中的作用。该研究将为阐明躁郁症的病理机制提供重要信息。

Bipolar disorder (BPD) is a common psychiatric illness with significant genetic contribution. The mechanism of its pathogenesis, though still unknown, is under extensive studies. We are the first to show at molecular and cell levels the relationship between circdaian clock and Bipolar disorder. By microarry profiling we found that the nephroblastoma overexpressed (Nov) gene is controlled by circadian clock and is cyclically expressed. It has very high expression level in the brain, especially the Suprachiasmatic Nucli where resides the master clock. Besides, Nov maps to a Bipolar susceptibility chromosome region (8q24.12) identified by multiple genetic linkage studies. We therefore selected the Nov gene as a candidate BPD susceptibility gene. We plan to study Nov's function in mice at molecular and behavoral levels using our newly generated mice that have conditional loss of function of the Nov gene. The molecular analysis will include examining circadian clock by realtime bioluminescense recording in cell or organotypic cultures derived from the Nov knockout mice. The behavioral tests include the wheel running test, the Open Field test, the Elevated Plus Maze test, and the Forced Swim test, to evaluate their circadian behavioral rhythms and their mood status. If any anomalies are observed, in vitro expressed human and mouse Nov protein, mood stabilizers [lithium, valproic acid (VPA), and carbamazepine (CBZ)] and Bipolar provoking drug [Prednisolone (PSL)] will be applied to verify Nov's function in Bipolar disorder. The significance of this study includes not only elucidating the functional role of Nov in regulating circadian clock, but also furthering our understanding of the pathogenic mechanism for BPD, therefore facilitating the establishment of new and more effective interventions for BPD.