权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional specialization of compartmentalized beta2-adrenergic signaling in neurons

神经元中β2-肾上腺素能信号传导的功能特化

基本信息

批准号：
9271247
负责人：
Nikoleta Georgieva Tsvetanova
金额：
$ 12.12万
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：
2016
资助国家：
美国
起止时间：
2016-05-10 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9271247
关键词：
Address Adrenergic Agents Adrenergic Receptor Agonist Alzheimer&apos s Disease Amino Acids Award Biochemical Brain CRISPR interference Cell Differentiation process Cell Nucleus Cell membrane Cell model Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Communication Critical Pathways Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dependency Down Syndrome Endocytosis Endosomes Foundations Future G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Expression Gene Silencing Genes Genetic Transcription Goals Grant Hippocampus (Brain)Ion Channel Learning Ligands Link Long-Term Potentiation Mass Spectrum Analysis Mediating Membrane Memory Memory Disorders Mental disorders Mentors Methods Modeling Molecular Neurons Neurosciences Norepinephrine Output Parkinson Disease Pathway interactions Phase Phosphorylation Physiological Post-Traumatic Stress Disorders Process Production Proteins Regulation Research Personnel Role Signal Pathway Signal Transduction Specificity Stable Isotope Labeling Synaptic plasticity System Testing Therapeutic Training Undifferentiated Vesicle Writing axon growth base career cell motility experimental study gene interaction genetic analysis genetic regulatory protein genome-wide high throughput analysis memory acquisition neurotransmitter release novel phosphoproteomics public health relevance receptor response skills spatiotemporal trafficking transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The beta2-adrenoceptor (β2-AR) is a G protein-coupled receptor (GPCR) that mediates physiological responses to noradrenaline in the brain and critically modulates long-term potentiation, synaptic plasticity and memory acquisition. Disturbances in this pathway have been implicated in mental illnesses such as Alzheimer's disease, Parkinson's disease, Down's syndrome, and post-traumatic stress disorder. Therefore, elucidating the molecular mechanisms that control β2-AR signaling and mediate its functional consequences in neurons will illuminate how cells execute critical brain functions and will enhance our ability to develop more specific and efficient therapies for memory disorders and mental illnesses. It was previously thought that β2- AR signaling occurred via cyclic AMP (cAMP) production strictly at the plasma membrane, but this canonical view has recently been challenged by evidence that ligand-dependent stimulation of β2-ARs also occurs on endosomes following agonist-induced endocytosis. I have demonstrated in HEK293 cells that endosomal β2- AR/cAMP signaling is selectively linked to the receptor-dependent transcriptional response, whereas the plasma membrane signal is effectively uncoupled from this response. My immediate goal is to investigate the functional consequences of compartmentalized β2-AR/cAMP signaling in primary neurons. My long-term goal is to understand how the spatiotemporal dynamics of β2-AR signaling contribute to higher-level neuronal functions. This K99/R00 award will allow me to achieve the following career goals: 1) gain training in neuroscience, 2) obtain additional training in high-throughput genetic analysis using CRISPR interference, 3) develop grant-writing, mentoring, and communication skills I will need in order to become a successful independent researcher. During the mentored phase of the award, I will determine if the transcriptional response to β2-AR activation in primary hippocampal neurons is governed by spatial encoding of cAMP signals (Aim 1). Next, I will systematically define the phosphoproteomic response to β2-AR signaling from distinct cellular compartments, and test the hypothesis that signaling from the plasma membrane (which does not efficiently activate transcription) preferentially stimulates phosphorylation of distinct neuronal target proteins (Aim 2). During the independent phase of the award, I will identify genes that regulate the spatial specificity of β2-AR signaling by conducting a large-scale CRISPR-based genetic analysis (Aim 3). The biochemical and systems-level analysis of β2-AR signaling accomplished with this award will help illuminate how the spatial regulation and molecular consequences of this pathway contribute to critical neuronal functions at the cellular level. Future studies based on these results will elucidate the precise mechanisms by which spatially biased signal transduction is achieved and investigate how the compartment-specific β2-AR/cAMP targets and the mechanisms that regulate them ultimately contribute to higher-level neuronal functions.