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Developing a Gene-Based Approach for Lasting Protection from Opioid Use Disorder

开发基于基因的方法来持久保护阿片类药物使用障碍

基本信息

批准号：
10641681
负责人：
Kelly Clemenza
金额：
$ 4.77万
依托单位：
ALBERT EINSTEIN COLLEGE 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：
2022-06-07 至 2025-06-06
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641681
关键词：
Affect Affinity Agonist Attenuated Behavior Behavioral Bilateral Binding Biological Assay Biosensor Brain Cells Coupled Data Correlations Development Disinhibition Dopamine Ectopic Expression Exhibits Failure Fentanyl Fiber Genes Goals Heroin Intervention Ligands Locomotion Logic Mediating Mental disorders Methods Modality Monitor Morbidity - disease rate Mus Mutation Neurons Nucleus Accumbens Opioid Opioid Peptide Pathway interactions Photometry Physiological Property Public Health Reaction Receptor Activation Receptor Inhibition Relapse Rewards Rotation Self Administration Signal Transduction Testing Therapeutic Therapeutic Uses Training Variant Ventral Tegmental Area Viral Vector Work addiction comorbidity designer receptors exclusively activated by designer drugs dopaminergic neuron effective intervention endogenous opioids fentanyl self-administration gamma-Aminobutyric Acid mortality mu opioid receptors mutant novel novel strategies opioid abuse opioid use disorder prevent receptor receptor expression response tool translational approach treatment strategy

项目摘要

PROJECT SUMMARY Opioid use disorders pose a substantial public health burden, with consistently high rates of morbidity and mortality. Though many interventions exist, all modalities suffer some degree of treatment nonadherence and response failure, which suggests a need for more effective solutions. When bound to Gi-coupled Mu opioid receptors (MuORs) in ventral tegmental area (VTA) GABAergic neurons, opioids cause disinhibition of VTA dopaminergic neurons, which then increases dopamine release in the nucleus accumbens (NAc), a key driver of reward signaling in the brain. Various methods of modulating VTA activity have been found to modify opioid-seeking behavior, but little work has been done to take this information in a therapeutic direction. Inspired by recent work using inhibitory DREADDs to attenuate heroin seeking behavior, this project seeks to utilize the MuOR itself as a means to inhibit reward signaling in a way that has clear translational value. The MuOR mutation D114(2.50)N is one of the best characterized variants of this receptor, and is known to exhibit a significant reduction in binding affinity and potency for various opioid ligands compared to the wild-type receptor. This mutant, which will be referred to as LAMuOR (Low Affinity Mu Opioid Receptor), may be exploited to create a genetically encoded tool that, when expressed in the VTA, inhibits the response of the reward pathway to exogenously administered opioids, while remaining unresponsive to endogenous ligands. Thus, the goal of this project is to test the hypothesis that LAMuOR suppresses opioid taking by responding preferentially to opioids of abuse – such as during fentanyl self-administration – while remaining unresponsive during physiological reward signaling. If successful, LAMuOR may ultimately prove to be a novel translational strategy by which a single treatment could confer life-long protection from opioid use disorders.

项目总结