Regulation of PSD phosphorylation and protein interactions networks by LTP

LTP 调节 PSD 磷酸化和蛋白质相互作用网络

基本信息

批准号：
9375377
负责人：
Marcelo Pablo Coba
金额：
$ 24.67万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9375377
关键词：
Address Adrenergic Agents Adrenergic beta-Agonists Autistic Disorder Bathing Bioinformatics Brain Diseases Cell physiology Complex Development Disease Excitatory Synapse Exposure to Frequencies Future Genes Genetic Glutamates Health Hippocampus (Brain)Impairment In Vitro Intellectual functioning disability Link Long-Term Potentiation Mass Spectrum Analysis Mediating Modeling Molecular Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Neurons Pattern Phosphorylation Phosphorylation Site Preparation Process Protein Kinase Protein Kinase Protein Phosphorylation Proteins Publishing Receptor Activation Regulation Research Role Sampling Signal Pathway Signal Transduction Site Slice Synapses Synaptic Transmission Synaptic plasticity Techniques Time beta-adrenergic receptor density experimental study mouse model mutant neuroregulation novel postsynaptic postsynaptic density protein protein activation protein complex ras GTPase-Activating Proteins

项目摘要

The activation of NMDAR by patterns of synaptic activity during long-term potentiation (LTP) is thought to regulate a number of protein kinases that potentiate synaptic transmission by phosphorylating proteins within the postsynaptic density (PSD). At the PSD of excitatory glutamatergic synapse, these phosphorylated proteins are thought to associate in protein interaction networks. These networks can convey important mechanism for processing, integrating and storing information at synapses in health and disease states. However, only a small number of phosphorylation sites are known. Moreover, there is no information on how NMDAR dependent high frequency stimulation-LTP modulates protein phosphorylation networks in temporal health and disease states. Our primary objectives here are to determine the temporal and NMDAR dependent phosphorylation networks triggered by the induction of LTP, and identify how synaptic stimulation in the presence of β-adrenergic receptor agonists regulates patterns of synaptic activity and protein interactions in the PSD, of both wild type and SynGAP mutant mice, a mouse model of intellectual disability. For this purpose we will use a combination of mouse hippocampus CA1 mini-slices, mass spectrometry, bioinformatics and mouse genetics. This will allow a better understanding of the role of the SynGAP mutation in the composition of PSD networks and the convergence of NMDAR and β-adrenergic receptors in LTP signaling networks and will inform future studies to be able to manipulate and regulate PSD signaling.

长期增强期间突触活动模式（LTP）激活NMDAR是被认为是调节许多蛋白激酶，这些激酶通过磷酸化的蛋白质来潜在的突触传播突触后密度（PSD）。在兴奋性谷氨酸能突触的PSD上，这些磷酸化蛋白被认为是蛋白质相互作用网络的关联。这些网络可以传达重要的机制在健康和疾病状态中的突触中处理，整合和存储信息。但是，只有一个已知少量的磷酸化位点。此外，没有有关NMDAR的信息依赖的高频刺激LTP调节临时健康中的蛋白质磷酸化网络疾病状态。我们这里的主要对象是确定临时和NMDAR依赖性磷酸化网络由LTP的诱导触发，并确定在存在β-肾上腺素能量的情况下如何突触刺激受体激动剂调节PSD中突触活性和蛋白质相互作用的模式，两种野生型和Syngap突变小鼠，一种智力障碍的小鼠模型。为此，我们将使用小鼠海马Ca1 mini线，质谱法的组合，生物信息学和小鼠遗传学。这将可以更好地理解syngap突变的作用在PSD网络的组成以及LTP中NMDAR和β-肾上腺素受体的收敛性中信号网络，并将告知未来的研究，以便能够操纵和调节PSD信号。