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Behavior-based discovery of small-molecule modulators of neurochemical signaling pathways that underlie addiction

基于行为的成瘾神经化学信号通路小分子调节剂的发现

基本信息

批准号：
10665084
负责人：
Christopher Fang-Yen
金额：
$ 60.5万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2022-07-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665084
关键词：
Address Affect Agonist Alcohol abuse Animals Behavior Behavior Control Behavioral Assay Biological Biological Assay Biological Process Brain Caenorhabditis elegans Calcium Coculture Techniques Collection Communities Complex Darkness Detection Dopamine Dopamine Receptor Drug abuse Drug resistance Epidemic Fractionation Functional Imaging Gait Gene Cluster Genes Genetic Goals Heart Hermaphroditism Image Impulsivity Libraries Link Locomotion Mass Spectrum Analysis Methods Microbe Microscopic Modeling Molecular Target Monitor Movement Natural Products Natural Source Nematoda Nervous System Neuromodulator Neuropeptides Neurophysiology - biologic function Pathology Pathway interactions Pharmacology Physiology Posture Process Psychopharmacology Psychotropic Drugs Reporting Reproductive Behavior Resources Rewards Risk Factors Role Serotonin Serotonin Antagonists Signal Pathway Signal Transduction Source Speed Stereotyped Behavior System Therapeutic addiction antagonist cellular targeting design egg genetic analysis imaging modality improved in vivo calcium imaging machine vision member metabolome microbial model organism motivated behavior mutant neural circuit neurochemistry novel optogenetics reward processing screening serotonin receptor side effect small molecule therapeutic target tool

项目摘要

PROJECT SUMMARY Addiction is a complex pathology of neural circuits that function in reward-processing, impulse control, and goal-directed behaviors. Small molecules targeting neuromodulator signaling pathways that function in these circuits are important therapeutics for the treatment of addiction. There is an urgent need to improve the pharmacology used to treat addiction. To address this need, we have developed methods that uses behavior- based screens to interrogate a novel source of natural products for effects on neuromodulator signaling in the nervous system of a microscopic animal - the nematode C. elegans. The natural products that we will screen are microbial metabolites that have eluded detection because they are not expressed under basal conditions but can only be elicited by environmental triggers. This microbial 'dark metabolome' contains small molecules with a wide variety of biological activities. These compounds have not yet been assayed for effects on the animal nervous system, and they constitute a rich and untapped resource for novel psychopharmacology. Through screens designed to demonstrate proof-of-concept, we have already identified compounds that strongly and specifically act on a circuit that uses neuropeptides and serotonin to generate behavior. We have also designed behavior-based screens for novel modulators of dopamine signaling. In addition to providing the opportunity to perform high-throughput behavior-based screens, the powerful genetics of the C. elegans model allows assignment of neuroactive compounds to specific neuromodulator signaling pathways. Successful completion of the aims of this project will generate enhanced and expanded libraries of novel natural products never before assayed for effects on the nervous system, identify novel small-molecule regulators of neural circuits, and match those compounds to specific neuromodulator signaling systems integral to the pathology of addiction.

项目总结