Characterization of Compartmentalized GPCR Signaling in Neurons

神经元区室化 GPCR 信号传导的表征

基本信息

批准号：
10636909
负责人：
Nikoleta Georgieva Tsvetanova
金额：
$ 38.91万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636909
关键词：
A kinase anchoring protein Address Adrenergic Receptor Behavior Biochemical Biological Models Biophysics Biosensor Brain Cell Nucleus Cell membrane Cells Cellular biology Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupling Cyclic AMP Data Development Endocytosis Endosomes Ferritin Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gases Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Heterodimerization Human Image Induced pluripotent stem cell derived neurons Learning Light Location Mediating Mediator Memory Memory Disorders Mental disorders Methods Microscopy Modeling Molecular Neurologic Neurons Neurosciences Outcome Output Pathway interactions Pharmacology Physiological Physiology Play Positioning Attribute Property Receptor Activation Receptor Inhibition Receptor Signaling Regulation Role Shapes Signal Transduction Site Specific qualifier value Synaptic plasticity System Testing Translational Regulation Translations Work cell type experimental study genome-wide improved insight interdisciplinary approach nervous system disorder neuropsychiatric disorder neurotransmission novel pharmacologic phosphoric diester hydrolase programs receptor receptor function response ribosome profiling transcriptional reprogramming transcriptome sequencing

项目摘要

More than a third of all G protein-coupled receptors (GPCRs) are expressed in the brain, where they modulate synaptic plasticity, memory and behavior, and also contribute to the pathophysiology of neuropsychiatric disorders. Therefore, improved understanding of how GPCRs several neurological and operate in neurons is fundamentally important to neuroscience, and will enable mechanism-based discovery of more selective and efficient therapies for memory disorders and mental illness. In this proposal, we build on our transformative finding that receptor activation on endosomal compartments underlies unique cellular responses. We propose to explore the molecular consequences of endosomal receptor signaling in neurons, and to investigate how neurons discriminate between distinct sites of local activation. We focus on the prototypical β2-adrenoceptor (β2-AR), a recognized mediator of neuronal function, to test the hypothesis that the molecular composition of signaling complexes present at endosomes is distinct from the plasma membrane resulting in unique neuronal outcomes upon β2-AR activation. We will employ an interdisciplinary approach in human iPSC-derived neurons to 1) delineate the consequences of compartmentalized β2-AR signaling on transcriptional reprogramming, 2) elucidate the role of plasma membrane- and endosomal β2-ARs in translational regulation of gene expression, and 3) determine how the endosome induces spatially biased GPCR responses. Successful completion of these studies will illuminate how spatial GPCR regulation is established, and how it shapes critical neuronal outputs of this pathway.

超过三分之一的 G 蛋白偶联受体 (GPCR) 在大脑中表达，它们在大脑中调节突触可塑性、记忆和行为，也有助于病理生理学因此，加深了对 GPCR 如何发挥作用的理解。一些神经系统和在神经元中运作的是对于神经科学来说至关重要，并将使得基于机制的发现更具选择性和在这项提案中，我们以我们的变革性疗法为基础。我们发现内体区室上的受体激活是独特的细胞反应的基础。探索神经元内体受体信号传导的分子后果，并研究如何神经元区分不同的局部激活位点。我们关注的是原型 β2-肾上腺素受体。（β2-AR），一种公认的神经功能调节剂，以检验以下假设：内体中存在的信号复合物与质膜不同，导致独特的神经元我们将在人类 iPSC 衍生的神经元中采用跨学科方法。 1) 描述区室化 β2-AR 信号转导对转录重编程的影响，2) 阐明质膜和内体 β2-AR 在基因表达翻译调控中的作用， 3) 确定内体如何诱导空间偏向的 GPCR 反应成功完成。研究将阐明空间 GPCR 调节是如何建立的，以及它如何塑造关键神经输出这条途径。