Regulation of postsynaptic protein interaction networks in complex brain disorders

项目总结： 突触后膜的信号规范称为突触后密度(PSD)，是 神经元中最复杂的信号机制。许多被认为有风险的基因 精神障碍的因素被认为影响PSD蛋白。然而，有了这些基因发现， 在定义导致PSD功能障碍的潜在生物学机制方面存在差距 复杂的脑部疾病。我们的主要目标是确定突变与精神分裂症之间的关系 (SCZ)，扰乱PSD的蛋白质相互作用网络(PIN)，风险因素是如何在功能上组织的 以及它们是如何由突触活动调节的。 我们将使用小鼠的遗传模型，包括蛋白激酶tnik和发现的shank3突变模型。 在患有SCZ的患者中，质谱分析、生化分析和计算方法 不仅探索PSD PIN在响应突触活动中的正常功能，而且还翻译人类 关于基因突变如何影响这个网络的功能的基因发现 精神疾病。

Project summary: The signaling specification of the post synaptic membrane known as the post-synaptic density (PSD), is one of the most complex signaling machineries in the neuron. Many of the genes that have been implicated as risk factors for the psychiatric disorders are thought to affect PSD proteins. Yet with these genetic discoveries, there has been a gap in defining underlying biological mechanisms that contribute to dysfunction at the PSD in complex brain disorders. Our primary objectives are to determine how mutations associated to schizophrenia (SCZ), disrupts protein interaction networks (PINs) at the PSD, how risk factors are functionally organized in PINs and how they are regulated by synaptic activity. We will use mouse genetic models, including the protein kinase TNiK and a mutant -model of SHANK3 found in patients with SCZ, mass spectrometry analysis, biochemical assays, and computational approaches to explore not only the normal function of PSD PIN in responding to synaptic activity, but also translate the human genetic findings into knowledge of how the function of this network is affected by mutations associated with psychiatric disease.