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Neuronal Gαi-GPCR targeting to primary cilia and impact on cAMP mediated transcription

神经元 Gαi-GPCR 靶向初级纤毛并对 cAMP 介导的转录产生影响

基本信息

批准号：
10040174
负责人：
Aliza Toby Ehrlich
金额：
$ 18.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040174
关键词：
Affinity Chromatography Behavioral Biosensor Brain Carrier Proteins Cell model Cells Cilia Cognitive Collection Corpus striatum structure Coupled Custom Cyclic AMP Cyclic AMP Receptors Cyclic AMP-Dependent Protein Kinases DNA Sequence Alteration DRD2 gene Data Development Disease Drug Targeting Environment Event Foundations Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GPER gene GTP-Binding Protein alpha Subunits, Gs Gene Expression Genetic Transcription Goals Hormones Human Image Impairment Knock-in Mouse Label Location Mass Spectrum Analysis Mechanics Mediating Methods Molecular Morphology Mus Neuromodulator Neurons Neurotransmitters Nuclear Obesity Organelles Pathway interactions Pharmaceutical Preparations Pharmacology Physiological Population Production Proteins Proteome Proteomics Receptor Activation Receptor Signaling Recombinants Research Proposals Second Messenger Systems Signal Transduction Signaling Protein Small Interfering RNA Stimulus Symptoms System Techniques Testing Tissues Training Venus Work base brain tissue cell type ciliopathy comparative developmental disease experience extracellular improved in vivo mu opioid receptors nervous system disorder neuronal cell body neuropsychiatric disorder neuropsychiatry neuroregulation novel novel therapeutic intervention receptor receptor function receptor-mediated signaling relating to nervous system response smoothened signaling pathway tool transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Ciliopathies are a collection of diseases that feature genetic mutations that impair primary cilia morphology or function and are characterized by symptoms that include developmental disorders, obesity, cognitive and behavioral deficits in humans. Primary cilia are immotile organelles that protrude off neuronal soma often adjacent to the nuclear compartment. A growing body of evidence indicates that extracellular stimuli (i.e., neuromodulators) transmits specialized signaling through G protein-coupled receptors (GPCRs) located on neuronal primary cilia to influence transcriptional changes and neuronal activity. Thus, determining how to specifically target neuronal ciliary GPCRs, will lead to novel therapeutic approaches for neurological and neuropsychiatric diseases. This proposal will focus on identifying selective ciliary targeting mechanics employed by neural Gαi-coupled GPCRs and the impact of ciliary GPCR signaling on gene transcription. We found that in brain sections, neural Gαi-coupled GPCRs, such as the mu opioid receptor, are expressed in neuronal primary cilia of some neuronal populations but not others suggesting cell and/or receptor-selective ciliary targeting machinery. In Specific Aim 1, we dissect whether ciliary targeting mechanics are cell-specific and/or receptor-selective in three distinct cell types. In Specific Aim 2, we employ Proteomics-based approaches to identify novel GPCR-associated proteins involved in ciliary targeting of Gαi-coupled GPCRs in cells and brain tissue. In Specific Aim 3, we will evaluate the contribution of ciliary Gαi-coupled GPCR cyclic-AMP signaling to neuronal transcription. Collectively, this proposal will attempt to discern the mechanisms underlying ciliary targeting of neuronal GPCRs and the neuromodulatory function of ciliary GPCRs.

项目总结/摘要纤毛病是一组疾病，其特征是基因突变损害初级纤毛形态或功能，并以包括发育障碍、肥胖、认知和人类的行为缺陷初级纤毛是从神经元索马体伸出的不动细胞器，靠近核室。越来越多的证据表明，细胞外刺激（即，神经调质）通过位于神经元上的G蛋白偶联受体（GPCR）传递专门的信号传导。神经元初级纤毛影响转录变化和神经元活性。因此，确定如何特异性靶向神经元睫状GPCR，将导致神经和神经精神疾病该提案将侧重于确定所采用的选择性纤毛靶向机制通过神经Gα i偶联GPCR和纤毛GPCR信号传导对基因转录的影响。我们发现，在脑切片中，神经Gα i偶联的GPCR，如μ阿片受体，表达在脑组织中。一些神经元群体的神经元初级纤毛，但其他人没有，表明细胞和/或受体选择性纤毛靶向机制。在特定目标1中，我们分析了纤毛靶向机制是否是细胞特异性的和/或在三种不同的细胞类型中具有受体选择性。在具体目标2中，我们采用基于蛋白质组学的方法鉴定参与细胞和脑中Gα i偶联GPCR纤毛靶向的新型GPCR相关蛋白组织.在具体目标3中，我们将评估纤毛Gα i偶联的GPCR环AMP信号转导对神经元转录总的来说，这项建议将试图辨别潜在的机制纤毛靶向神经元GPCR和睫状GPCR的神经调节功能。