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Regulation of postsynaptic protein interaction networks in complex brain disorders

复杂脑部疾病中突触后蛋白质相互作用网络的调节

基本信息

批准号：
10493636
负责人：
Marcelo Pablo Coba
金额：
$ 7.51万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493636
关键词：
Affect Biochemical Biological Biological Assay Brain Diseases Candidate Disease Gene Chemicals Complex Computer Analysis Data Development Disease Etiology Excitatory Synapse Family Functional disorder Genes Genetic Genetic Models Genetic Variation Genomic approach Goals Hippocampus (Brain)Human Genetics Individual Knowledge Life Long-Term Potentiation Mass Spectrum Analysis Mediating Mental disorders Modeling Molecular Mus Mutation Neurons Pathway interactions Patients Phosphorylation Physiological Productivity Protein Kinase Proteins Public Health Regulation Research Risk Factors Role Scaffolding Protein Schizophrenia Signal Transduction Site Societies Synapses Synaptic Membranes Testing Translating Variant Wild Type Mouse density genetic variant insight mouse genetics mutant new therapeutic target patient stratification postsynaptic response risk variant schizophrenia risk synaptic function treatment strategy

项目摘要

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.

项目概要：突触后膜的信号传导规范称为突触后密度 (PSD)，是其中之一神经元中最复杂的信号传导机制。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如何与精神分裂症相关（SCZ），破坏 PSD 处的蛋白质相互作用网络（PIN），风险因素如何在功能上组织 PIN 及其如何受突触活动调节。我们将使用小鼠遗传模型，包括蛋白激酶 TNiK 和发现的 SHANK3 突变模型 SCZ 患者的质谱分析、生化检测和计算方法不仅探索 PSD PIN 在响应突触活动中的正常功能，而且还翻译了人类基因发现了解该网络的功能如何受到与相关突变的影响精神疾病。