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Precision pharmacology by local control of opioid receptors in neural circuits

通过局部控制神经回路中的阿片受体实现精准药理学

基本信息

批准号：
10044383
负责人：
Aashish Manglik
金额：
$ 44.33万
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：
2020-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044383
关键词：
Absence of pain sensation Acute Agonist Analgesics Behavioral Brain Breathing Cytoplasm Dangerousness Development Electrophysiology (science)Enkephalins G-Protein-Coupled Receptors Goals Heroin Heterogeneity Hyperalgesia Location Mediating Membrane Methods Modeling Molecular Morphine Mus Neurons Neuropeptides Nociception Opiate Addiction Opioid Opioid Peptide Opioid Receptor Pathologic Peptides Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physiological Preparation Proteins Psychological reinforcement Receptor Activation Receptor Signaling Recombinant adeno-associated virus (rAAV)Resolution Series Signal Transduction Slice Spinal Cord System Technology Testing Therapeutic Therapeutic Index Time Tissues Ventilatory Depression base behavioral response clinically relevant comparative efficacy drug action efficacy testing endogenous opioids high risk improved in vivo insight instrument mu opioid receptors nanobodies neural circuit neuroregulation novel optogenetics programs receptor receptor function recruit side effect tool

项目摘要

PROJECT SUMMARY This proposal seeks to leverage the emerging understanding of cellular and subcellular heterogeneity in opioid signaling for therapeutic discovery. The project develops new optogenetic and chemogenetic tools to achieve local control of opioid receptor activity and signaling in neural circuits and at a subcellular level of resolution. The proposal seeks to develop a versatile toolbox and provide proof-of-concept for "in vivo precision pharmacology" that have not yet been applied to the opioid system. The first phase (R61) is a "high-risk" technology enabling phase, based on combining our collaborative team's expertise in developing receptor-blocking intracellular nanobodies with established methods for conferring local control of nanobody concentration in the cytoplasm and specific membrane domains, using optogenetic and chemogenetic strategies that have already been validated but never before applied to opioid receptors. The R61 phase will develop these tools (Specific Aim 1) and validate them in neuronal culture and acute slice preparations (Specific Aim 2). These studies will provide not only proof-of-concept for in vivo precision pharmacology of opioid receptors, but also for G protein-coupled receptors as a class. We have set a specific series of milestones to evaluate progress, and to assess feasibility for advance to in vivo studies. If the milestones are successfully met, the second phase (R33) will apply the new tools to selectively target opioid signaling in neural circuits in vivo, focusing on analgesia, behavioral reinforcement and respiratory depression by clinically relevant opioid drugs. Mice are used as a well-established and relevant model (Specific Aim 3). These studies leverage the combined expertise of our collaborative team, and will establish powerful optogenetic and chemogenetic manipulations for the study of in vivo opioid function for the first time. Accordingly, the proposed studies to provide the first-in-class application of optogenetic and chemogenetic control to the opioid system in vivo, and they will explore a precision pharmacology of opioids based on location in neural circuits.

项目总结