Elucidating the effect of Disc1 on neurodevelopment and synaptic transmission

描述（由申请人提供）：最近的遗传研究为精神疾病中的基因Disrupted-in-Schizophrenia-1（DISC 1）提供了强有力的支持。主要通过体外研究获得的其他数据表明，DISC 1可能通过与其他蛋白质（包括核分布E样（NUDE-L）蛋白和磷酸二酯酶4 B）相互作用在神经发育和细胞信号传导中发挥关键作用。尽管DISC 1功能的研究取得了最新进展，但仍有几个关键问题没有得到解决。我们建议利用我们在实验室中建立的独特而可靠的小鼠模型，该模型密切模仿在受影响家庭中观察到的易位，同时保留内源性蛋白质水平，以便于更好地了解DISC 1在正常和异常大脑发育和功能中的生理作用。我们的主要目标是a）促进更好地理解DISC 1在神经发育以及突触传递和可塑性中的贡献，和B）测试现有的体外结果是否可以在我们建立的小鼠模型中体内验证。我们的分析有望为DISC 1增加精神疾病风险的方式提供有价值的见解，同时提供一个表征良好的动物模型，可用于测试进一步的假设并促进未来的药物开发工作。

DESCRIPTION (provided by applicant): Recent genetic studies provide strong support for the gene Disrupted-in-Schizophrenia-1 (DISC1) in mental illness. Additional data obtained primarily by in vitro studies suggested that DISC1 may play a key role in neurodevelopment and cell signaling by interacting with other proteins, including nuclear distribution E-like (NUDE-L) protein and phosphodiesterase 4B. Despite recent advances in the study of DISC1 function, several critical issues remain unanswered. We propose to utilize a unique and reliable mouse model that we have established in our laboratory, which closely mimics the translocation observed in an affected family while preserving endogenous proteins levels, in order to facilitate a better understanding of the physiological contribution of DISC1 in normal and abnormal brain development and function in the context of psychiatric disorders. Our main goals are to a) facilitate a better understanding of the contribution of DISC1 in neurodevelopment, as well as in synaptic transmission and plasticity and b) test whether existing in vitro results can be validated in vivo in the mouse model we have established. Our analysis promises to provide valuable insights into the ways DISC1 increases the risk of psychiatric disorders and at the same time provide a well-characterized animal model that can be used to test further hypotheses and facilitate future drug development efforts.