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.

项目摘要阿片类药物使用障碍造成了大量的公共卫生伯恩（Burnen），发病率始终高和死亡率。尽管存在许多干预措施，但所有方式都遭受了一定程度的治疗不遵守和反应失败，这表明需要更有效的解决方案。当绑定到胃肠道偶联的Mu Oopioid时腹侧对盖区域（VTA）GABA能神经元中的受体（MUOR），阿片类药物会引起VTA的抑制作用多巴胺能神经元，然后增加了伏隔核（NAC）的多巴胺释放，这是一个关键驱动器大脑中的奖励信号。已经发现各种调节VTA活性的方法可以修改寻求阿片类药物的行为，但是几乎没有完成将这些信息朝着治疗方向采用的工作。受到最近使用抑制性恐怖来衰减海洛因寻求行为的工作的启发，该项目试图利用MUOR本身作为具有清晰翻译价值的方式抑制奖励信号的一种手段。 MUOR突变D114（2.50）n是该受体的最佳特征变体之一，是与野生型受体。这个突变体，称为lamuor（低亲和力mu阿片受体），可以探索以创建一个普遍编码的工具，该工具在VTA中表达时会抑制外源给予阿片类药物的奖励途径，同时对内源性无反应配体。这是该项目的目的是检验Lamuor抑制阿片类药物服用的假设优先应对虐待的opioid，例如在芬太尼自我管理期间在身体奖励信号传导过程中无反应。如果成功的话，Lamuor最终可能被证明是一本小说单一治疗可以赋予阿片类药物使用障碍的终生保护的翻译策略。