Regulation of postsynaptic protein interaction networks in complex brain disorders

项目概要： 被称为突触后密度（PSD）的突触后膜的信号传导特化是以下之一： 神经元中最复杂的信号机制。许多与风险有关的基因 精神疾病的因素被认为会影响PSD蛋白。然而，随着这些基因的发现， 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与精神分裂症相关的突变 (SCZ)，破坏PSD的蛋白质相互作用网络（PIN），风险因素在功能上是如何组织的， PIN以及它们如何受突触活动的调节。 我们将使用小鼠遗传模型，包括蛋白激酶TNiK和SHANK3的突变模型， 在SCZ患者中，质谱分析，生化测定和计算方法， 不仅可以探讨PSD PIN在响应突触活动中的正常功能， 遗传学发现转化为关于该网络的功能如何受到与以下相关的突变影响的知识： 精神病

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.