Molecular Neurobiology of Human Opioid Use Disorder

人类阿片类药物使用障碍的分子神经生物学

基本信息

批准号：
10595619
负责人：
YASMIN L. HURD
金额：
$ 54.22万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595619
关键词：
Address Anatomy Animal Model Animals Area Autopsy Behavior Biochemical Biological Biological Assay Brain Brain region Cell Culture Techniques Cells Characteristics Chronic Cognitive deficits Communities Corpus striatum structure Cytoskeletal Modeling Cytoskeleton Data Dedications Development Disease Dorsal Drug Prescriptions Economic Burden Epidemic Epigenetic Process FYN gene Female Fluorescence Foundations Functional disorder Future Gene Expression Glutamates Goals Harm Reduction Health Healthcare Heavy Drinking Helping to End Addiction Long-term Heroin Heroin Abuse Heroin Dependence Human Impairment In Situ Hybridization In Vitro Intervention Investigation Knowledge Link Mediating Medical Microtubules Modeling Molecular Molecular Neurobiology Molecular Profiling Molecular Target Motivation N-Methylaspartate Neurobiology Neurons Nuclear Opiate Addiction Opioid Overdose Pathology Patients Pharmaceutical Preparations Phosphorylation Phosphorylation Site Rattus Recording of previous events Regulation Relapse Research Resources Rewards Rodent Rodent Model Role Science Self Administration Services Signal Pathway Signal Transduction Sorting Specificity System Time Translational Research United States United States National Institutes of Health Up-Regulation Viral Withdrawal abuse liability addiction care burden cell type cognitive function density drug abuser glutamatergic signaling grasp heroin abuser heroin use human subject hyperphosphorylated tau inhibitor insight knock-down male multidisciplinary non-opioid analgesic novel novel therapeutics opioid abuse opioid epidemic opioid exposure opioid overdose opioid use opioid use disorder overdose death pharmacologic postsynaptic prescription opioid promoter src-Family Kinases targeted treatment tau Proteins tau-1 therapeutic development tool transcriptome transcriptome sequencing translational potential transmission process

项目摘要

Project Summary Opioid addiction is a national epidemic contributing to the deadliest drug overdose crisis in US history and accompanied by excessive healthcare burdens due to the misuse of heroin and opioid prescription medications. There continues to be a lack of neurobiological knowledge about opioid use disorder to drive novel therapies critically needed to provide options to the current medications that are predominantly opioid-based and thus of abuse liability themselves. A fundamental core of our reverse translational research efforts has been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Through such strategies we recently discovered a previously unrecognized neurobiological impact of opioids suggesting opioid-induced epigenetic alteration linked to the FYN which mediates glutamatergic signaling and phosphorylates tau (pTau); we also detected significant glutamatergic alterations and hyper-pTau pathology in heroin abusers. FYN is a Src family tyrosine kinase within the postsynaptic density that phosphorylates tau, involved in microtubule stability and dynamics, and thus a regulator of cytoskeletal remodeling which is a key feature of addiction. We verified elevation of FYN-targeted Tau phosphorylation in rats that self-administered heroin and in our chronic opioid in vitro cell culture model. Moreover, we were able to inhibit heroin self-administration (SA) and seeking behaviors in animals treated with a Fyn inhibitor and Fyn knockdown. These multidisciplinary and integrative data provides a strong foundation on which to interrogate FYN in opioid abuse with the goal of therapeutic development. We hypothesize that upregulation of Fyn and its resulting downstream target impairments in mesocorticolimbic brain areas contribute to heroin addiction behavior and can be targeted for treatment interventions. We propose to (1) determine the molecular signature of FYN-related networks in mesocorticolimbic regions associated with heroin abuse by RNA-sequencing in a cell-specific manner in human and the rat heroin SA model and to (2) characterize cell-specific downstream alterations mediated by Fyn underlying heroin SA and seeking behaviors. The downstream mechanisms leverage viral mediated cell-specific effects of Fyn on intracellular signaling cascades and pTau as well as cytoskeletal organization. Results gained from our integrative multidisciplinary study will advance knowledge of Fyn-related abnormalities underlying opioid abuse and provide science-based pharmacotherapeutic targets to expand treatment options for opioid addiction.

项目概要阿片类药物成瘾是一种全国性流行病，导致美国历史上最致命的药物过量危机由于滥用海洛因和阿片类处方药，还伴随着过度的医疗负担。仍然缺乏关于阿片类药物使用障碍的神经生物学知识来推动新疗法迫切需要为目前主要以阿片类药物为主的药物提供选择，因此滥用责任本身。我们逆向转化研究工作的一个基本核心是填补关键问题通过直接调查人类海洛因滥用者的大脑来弥补知识差距。通过这样的策略我们最近发现了阿片类药物先前未被认识的神经生物学影响，表明阿片类药物引起的与 FYN 相关的表观遗传改变，FYN 介导谷氨酸信号传导并磷酸化 tau (pTau)；我们还在海洛因滥用者中发现了显着的谷氨酸能改变和高 pTau 病理学。 FYN 是 Src 突触后密度中的家族酪氨酸激酶，磷酸化 tau，参与微管稳定性和动力学，因此是细胞骨架重塑的调节者，这是成瘾的一个关键特征。我们核实了在自我施用海洛因的大鼠和我们的慢性阿片类药物中，FYN 靶向的 Tau 磷酸化升高体外细胞培养模型。此外，我们能够抑制海洛因自我给药（SA）和寻求行为在用 Fyn 抑制剂和 Fyn 敲低治疗的动物中。这些多学科和综合数据提供了为审问 FYN 滥用阿片类药物以实现治疗开发的目标奠定了坚实的基础。我们假设 Fyn 的上调及其导致的中皮质边缘脑下游目标损伤这些区域会导致海洛因成瘾行为，并可作为治疗干预的目标。我们建议（1）确定与海洛因相关的中皮质边缘区域 FYN 相关网络的分子特征通过 RNA 测序以细胞特异性方式在人和大鼠海洛因 SA 模型中进行滥用，并 (2) 表征 Fyn 介导的细胞特异性下游改变潜在的海洛因 SA 和寻求行为。这下游机制利用病毒介导的 Fyn 对细胞内信号级联的细胞特异性作用和 pTau 以及细胞骨架组织。我们的综合多学科研究获得的结果将增进对阿片类药物滥用的 Fyn 相关异常的了解，并提供基于科学的信息药物治疗目标扩大阿片类药物成瘾的治疗选择。