Elucidating the effect of Disc1 on neurodevelopment and synaptic transmission

描述（由申请人提供）：最近的遗传学研究为精神疾病中的DISC1基因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，DISC1可能通过与其他蛋白质（包括核分布样蛋白（NUDE-L）蛋白和磷酸二酯酶4B）相互作用，在神经发育和细胞信号传导中发挥关键作用。尽管最近对DISC1功能的研究取得了进展，但几个关键问题仍未得到解答。我们建议利用我们在实验室建立的独特而可靠的小鼠模型，该模型在保留内源性蛋白质水平的同时，密切模仿受影响家庭中观察到的易位，以便更好地理解DISC1在精神疾病背景下正常和异常大脑发育和功能中的生理贡献。我们的主要目标是：a)更好地理解DISC1在神经发育、突触传递和可塑性中的作用；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得到验证。我们的分析有望为DISC1增加精神疾病风险的方式提供有价值的见解，同时提供一个具有良好特征的动物模型，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.