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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.

摘要 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。对神经回路功能的深远影响。它们在调节动机、奖励、疼痛、负面影响和压力反应，这些在物质使用障碍的背景下都很重要（SUD）。已经显示几种GPCR的外源性配体可以改变药物寻求行为，产生了对GPCR作为开发药物治疗剂的目标的兴趣，使用障碍。哺乳动物大脑中有超过300种不同的非感觉GPCR，对所有这些人来说，根本问题仍然没有答案。例如，一个给定的受体的能力如何激活不同的G蛋白亚型（Gi/o，Gs，Gq，G12/13）在神经解剖区域，细胞类型，和亚细胞区域这些特性是如何在慢性药物使用、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 蛋白亚型特异性我们的方法只需要普通的神经科学设备（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在健康和患病大脑中的许多GPCR上，并加速针对成瘾中的GPCR的努力。