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.

项目摘要阿片类药物成瘾是一种全国流行病，导致了美国历史上最致命的药物过量危机和由于滥用海洛因和阿片类药物处方药，伴随着过多的医疗保健负担。仍然缺乏有关阿片类药物使用障碍的神经生物学知识来推动新疗法至关重要的是为当前主要基于阿片类药物的药物提供选择虐待责任本身。我们反向翻译研究工作的基本核心是填补关键通过直接调查人类海洛因滥用者的大脑的知识差距。通过这样的策略我们最近发现了阿片类药物的先前未识别的神经生物学影响，提示阿片类药物诱导与介导谷氨酸能信号传导并磷酸化tau（PTAU）相关的FYN相关的表观遗传改变；我们还检测到海洛因滥用者中的重大谷氨酸能改变和超普通病理。 Fyn是SRC 在突触后密度中磷酸化的tau的家族酪氨酸激酶，参与微管稳定性和动力学，因此是细胞骨架重塑的调节剂，这是成瘾的关键特征。我们验证了自我管理的海洛因和我们的慢性阿片类药物的大鼠中靶向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管理（SA）并寻求行为在用Fyn抑制剂和Fyn敲低处理的动物中。这些多学科和综合数据提供了在阿片类药物滥用方面审问Fyn的坚定基础，以治疗性发展的目标。我们假设FYN的上调及其在中皮质胶质大脑中产生的下游目标障碍领域有助于海洛因成瘾行为，可以针对治疗干预措施。我们建议（1）确定与海洛因相关的中质膜区域中FYN相关网络的分子特征通过人类和大鼠海洛因SA模型以特定于细胞的方式进行RNA滥用，并以（2）为特征 Fyn介导的海洛因SA介导并寻求行为。这下游机制利用FYN对细胞内信号级联的病毒介导的细胞特异性作用和PTAU以及细胞骨架组织。从我们的综合多学科研究中获得的结果将提前了解FYN相关异常的阿片类药物滥用并提供基于科学的异常药物治疗靶标，以扩大阿片类药物成瘾的治疗选择。