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Postsynaptic roles of ankyrins

锚蛋白的突触后作用

基本信息

批准号：
10629210
负责人：
Peter Penzes
金额：
$ 63.98万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629210
关键词：
ANK2 gene ANK3 gene Ankyrin Repeat Ankyrins Axon Behavior Behavioral Biochemical Bioinformatics Biological Process Biology Bipolar Disorder Brain Brain Diseases Calcium Cell membrane Cellular biology Central Nervous System Complex Data Dendrites Deubiquitination Development Family Study Funding Funding Opportunities Future GTP-Binding Proteins Genes Genome Glutamates Homer 1 Human Hybrids Image In Vitro Intellectual functioning disability Knock-out Knockout Mice Laboratories Maintenance Methods Molecular Biology Morphology Mus Mutation Neurobiology Neurodevelopmental Disorder Neurons Pathogenicity Pattern Phenotype Plasmids Play Positioning Attribute Process Proteins Proteomics Reagent Regulation Reporter Research Rodent Role Schizophrenia Site Structure Susceptibility Gene Synapses Synaptosomes Testing Time Transforming Growth Factor beta United States National Institutes of Health Variant Vertebral column Yeasts autism spectrum disorder cell type conditional knockout endocannabinoid signaling exome sequencing frontal lobe genome-wide in vivo mouse model neuroproteomics neuropsychiatric disorder novel palmitoylation postsynaptic rare variant risk variant scaffold spatiotemporal synaptic function two photon microscopy ubiquitin isopeptidase ultra high resolution

项目摘要

ABSTRACT Extensive evidence implicates glutamatergic synapses as key pathogenic sites in neuropsychiatric disorders (NPDs). Recently-emerging evidence has implicated ankyrin proteins, including Ankyrin-G (AnkG), encoded by the ANK3 gene, and Ankyrin-B (AnkB), encoded by ANK2, in the biology of central nervous system synapses. While conventionally AnkG and –B have been seen as playing roles mainly at the axon initial segment, their functions in central glutamatergic synapses have only begun to be investigated, including in studies initiated by our laboratory. During the previous funding period, we have made extensive progress in understanding the regulation and interactome of AnkG at synapses and in dendrites. Our preliminary findings broaden our understanding of the neurobiology of ankyrins, and implicate them in several novel process, including deubiquitination and endocannabinoid signaling. In this proposal we will use neuroproteomics, conditional knockout and reporter mice, super-resolution and in vivo two-photon microscopy, calcium imaging, bioinformatics, and behavioral analyses, to investigate the functions of AnkG's protein partners in dendrite and at glutamatergic synapses. We hypothesize that AnkG performs multiple novel functions including supramolecular scaffold complex maintenance and regulation of endocannabinoid signaling, through which it controls spiny synapse development, structure, function, as well as circuit level network activity and behavior, in a cell type and developmental period-specific manner. We will test this hypothesis in the following Aims: Aim 1. To investigate the impact of cell type-dependent and developmentally-timed knock out of AnkG on brain structure, function, and behavior across maturation. Aim 2. To investigate the impact of cell type-dependent and developmentally-timed knock out of AnkB on brain structure, function, and behavior across maturation. Aim 3. To determine the mechanisms and functional significance of the interaction of AnkG with DAGLĮ. The proposed studies are highly novel and impactful, given that the synaptic functions of ankyrins are only beginning to be investigated. This proposal will be the first to investigate the function of several recently-discovered AnkG-interacting proteins in unexpected biological processes, using multiple cutting edge methods, and will open new avenues for many future studies.

摘要