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

• 批准号: 10156628
• 负责人: YASMIN L. HURD
• 金额: $ 60.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10156628
• 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; Data; Development; Disease; Dorsal; Drug Prescriptions; 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; Pharmacology; 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 - Cell Movement; Specificity; System; Time; Translational Research; United States; United States National Institutes of Health; Up-Regulation; Viral; Withdrawal; addiction; base; cell type; cognitive function; density; drug abuser; glutamatergic signaling; healing; heroin abuser; heroin use; human subject; hyperphosphorylated tau; inhibitor/antagonist; 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; postsynaptic; prescription opioid; promoter; src-Family Kinases; targeted treatment; tau Proteins; tau phosphorylation; tau-1; therapeutic development; tool; transcriptome; transcriptome sequencing

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.

项目摘要 阿片成瘾是一种全国性的流行病，导致了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而造成过度的医疗负担。 仍然缺乏关于阿片类药物使用障碍以驱动新疗法的神经生物学知识 迫切需要为目前主要以阿片类药物为基础的药物提供选择，因此 滥用责任本身。我们反向翻译研究工作的一个基本核心是填补关键的 通过直接调查人类海洛因滥用者的大脑，了解知识差距。通过这些战略，我们 最近发现了一种先前未知的阿片类药物的神经生物学影响，表明阿片类药物诱导 表观遗传学改变与FYN有关，它介导谷氨酸能信号转导并磷酸化tau(Ptau)； 我们还在海洛因滥用者中检测到显著的谷氨酸能改变和高ptau病理。Fyn是一名高级员工 突触后密度内的家族酪氨酸激酶参与微管的稳定性 和动力学，因此是细胞骨架重塑的调节器，这是成瘾的一个关键特征。我们核实了 自服海洛因大鼠和慢性阿片类药物大鼠体内FYN靶向Tau磷酸化水平的升高 体外细胞培养模型。此外，我们还能够抑制海洛因自我给药(SA)和寻找行为 在用Fyn抑制剂和Fyn基因敲除治疗的动物中。这些多学科的综合数据提供了 为审问FYN的阿片类药物滥用提供了坚实的基础，以实现治疗开发的目标。我们 Fyn基因上调及其导致的边缘皮质中脑靶向损伤假说 地区是海洛因成瘾行为的诱因，可以作为治疗干预的目标。我们建议(1) 确定海洛因相关皮质边缘区FYN相关网络的分子特征 在人和大鼠海洛因SA模型中以细胞特异性方式进行RNA测序的滥用及其(2)特征 由Fyn介导的细胞特异性下游改变是海洛因SA和寻找行为的基础。这个 下游机制利用病毒介导的细胞特异性Fyn对细胞内信号级联的影响 和ptau以及细胞骨架组织。我们多学科综合研究的成果将 增进对阿片类药物滥用背后与FYN相关的异常的了解，并提供科学依据 药物治疗目标，以扩大阿片成瘾的治疗选择。