High Content Functional Neuroanatomy of Endogenous GPCRs

内源性 GPCR 的高内涵功能神经解剖学

基本信息

批准号：
10588941
负责人：
Patrick Ross O'Neill
金额：
$ 23.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588941
关键词：
Acceleration Agonist Anatomy Animal Behavior Antibodies Autoradiography Behavior Binding Biochemical Biological Assay Biosensor Biotin Brain Brain Diseases Chronic Chronic stress Color Complex Data Development Drug usage Equipment Exhibits Fc Receptor Fluorescence G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Goals Heating Image Immunohistochemistry In Situ Intervention Ligands Ligation Link Location Measurement Measures Mediating Metabotropic Glutamate Receptors Methods Modeling Modification Molecular Motivation Mus National Institute of Drug Abuse Neuroanatomy Neurosciences Nucleotides Opioid Receptor Pain Pattern Pharmaceutical Preparations Pharmacological Treatment Play Property Publishing Rattus Reagent Resolution Rewards Role Sensory Signal Transduction Specificity Stress Substance Use Disorder Synaptic Transmission System Testing Therapeutic Tissue Fixation Tissues Withdrawal addiction anatomic imaging biological adaptation to stress cannabinoid receptor cell type chronic pain cryostat drug of abuse drug seeking behavior experimental study fluorescence microscope imaging modality innovation insight interest laboratory equipment mu opioid receptors negative affect neural circuit neuronal excitability neurotransmitter release nonhuman primate novel novel therapeutics opioid use disorder optogenetics pharmacologic protein activation ratiometric receptor receptor coupling receptor function response success temporal measurement tool virtual

项目摘要

Abstract G protein coupled receptors (GPCRs) modulate neuronal excitability and neurotransmitter release, and exert profound effects on neural circuit functions. They play important roles in regulating motivation, reward, pain, negative affect, and stress responses, which are all important in the context of substance use disorders (SUDs). Exogenous ligands for several GPCRs have been shown to modify drug seeking behavior, which has generated interest in GPCRs as targets for the development of pharmacological therapeutics for substance use disorders. There are over 300 different non-sensory GPCRs expressed in mammalian brains, and fundamental questions remain unanswered for all of them. For example, how does a given receptor's ability to activate different G protein subtypes (Gi/o, Gs, Gq, G12/13) vary across neuroanatomical regions, cell types, and subcellular regions? How are these properties altered in response to chronic drug use, chronic stress, or chronic pain? To help answer these questions, we will develop new imaging methods in tissue sections for neuroanatomical measurement of GPCR-mediated G protein activation, with subcellular resolution and G protein subtype specificity. Our methods will only require common neuroscience equipment (cryostats and fluorescence microscopes) and commercially available reagents. They will generate high-content information on many GPCRs in healthy and diseased brains, and accelerate efforts to target GPCRs in addiction.

抽象的 G 蛋白偶联受体 (GPCR) 调节神经元兴奋性和神经递质释放，并发挥作用对神经回路功能产生深远影响。它们在调节动机、奖励、痛苦、负面情绪和压力反应，这些对于药物滥用障碍都很重要（泡沫）。多种 GPCR 的外源配体已被证明可以改变药物寻求行为，这已被证实引起了人们对 GPCR 作为药物治疗药物开发靶标的兴趣使用障碍。哺乳动物大脑中表达了 300 多种不同的非感觉 GPCR，并且他们所有人的基本问题仍未得到解答。例如，给定受体的能力如何激活不同的 G 蛋白亚型（Gi/o、Gs、Gq、G12/13）因神经解剖区域、细胞类型、和亚细胞区域？这些特性如何因长期吸毒、慢性压力或慢性疼痛？为了帮助回答这些问题，我们将开发新的组织切片成像方法 GPCR 介导的 G 蛋白激活的神经解剖学测量，具有亚细胞分辨率和 G 蛋白质亚型特异性。我们的方法只需要常见的神经科学设备（低温恒温器和荧光显微镜）和市售试剂。他们将产生高内容的信息健康和患病大脑中的许多 GPCR，并加速针对成瘾中的 GPCR 的努力。