Neuronal exosomes in cocaine abuse and treatment response in socially housed monkeys

社会饲养的猴子可卡因滥用和治疗反应中的神经元外泌体

• 批准号: 10609495
• 负责人: Gagan Deep
• 金额: $ 38.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609495
• 关键词: Abstinence; Alcohol abuse; Bioinformatics; Biological; Biological Markers; Biology; Biometry; Blood; Brain; Cells; Cerebrospinal Fluid; Cessation of life; Chronic; Clinical; Cocaine; Cocaine Abuse; Cocaine use disorder; Data; Diameter; Dopamine; Dopamine Receptor; Drug abuse; Failure; Female; Funding; Future; Goals; Heroin Abuse; Individual Differences; Intravenous; Laboratories; Lipids; Liquid substance; Macaca fascicularis; Measures; Metabolic; Modeling; Molecular; Molecular Profiling; Monkeys; National Institute of Drug Abuse; Neurons; Organism; Parents; Pathologic; Pharmaceutical Preparations; Physiological; Plasma; Positron-Emission Tomography; Predisposition; Preventive; Prognostic Marker; Proteins; Psychological reinforcement; Public Health; RNA; Relapse; Research Personnel; Research Proposals; Saliva; Same-sex; Sampling; Sex Differences; Social Hierarchy; Social Problems; Stress; Symptoms; Testing; Treatment Efficacy; Treatment outcome; United States; Vulnerable Populations; Work; behavior test; biomarker identification; cell type; cocaine self-administration; cocaine use; cognitive testing; cost; cost effective; diagnostic biomarker; differential expression; efficacy testing; exosome; male; methamphetamine abuse; molecular marker; multidisciplinary; multiple omics; nanovesicle; nervous system disorder; neuroimaging; nonhuman primate; novel; personalized medicine; pharmacologic; receptor; receptor function; sex; social; social group; success; targeted treatment; tool; treatment response; vesicular release

Project Summary/Abstract Cocaine use disorder (CUD) continues to be a major public health and social problem in the United States. A hallmark of CUD is individual differences in vulnerability, relapse and treatment efficacy. Our overall goal is to achieve a better understanding of individual differences in the long-term consequences of the reinforcing effects of cocaine using a unique nonhuman primate model of CUD. We propose to use neuronal-derived exosomes (NDE) in the blood to identify molecular biomarkers associated with an individual's vulnerability to cocaine abuse, susceptibility to relapse following abstinence, and success or failure of targeted therapies for cocaine abuse. Exosomes are nano-vesicles that are released by all cell types. Those released by cells under stressed or pathologic states are different from those released under normal physiologic conditions. Taking advantage of this difference, several exosome-based diagnostic and prognostic biomarkers have been successfully developed. Recent studies have also shown that exosomes in biofluids can be used to establish molecular signatures associated with methamphetamine, heroin, and alcohol abuse. However, exosomes have not been used to understand cocaine abuse – the focus of this application. The proposed study capitalizes on a timely opportunity to use plasma samples from an ongoing NIDA-funded study (R01 DA017763-11; PI: Nader) to understand cocaine abuse in socially housed female and male monkeys. The parent study is testing the efficacy of several pharmacological agents thought to work differently in dominant and subordinate female and male monkeys. All monkeys (socially housed and naturally forming dominant and subordinate hierarchies) are undergoing comprehensive behavioral and cognitive testing, and neuroimaging of central dopamine D2/D3 receptor (D2/D3R) availability using positron emission tomography (PET) imaging. With the costs of key measures covered by existing funding, the availability of plasma samples from these monkeys offers a valuable and cost-effective opportunity to advance our understanding of how exosomes could provide a non- invasive molecular tool to inform us about cocaine abuse and treatment outcomes. Pilot and feasibility data (a) validate our ability to isolate and characterize NDEs from stored plasma samples, and (b) support the utility of NDE biomarkers to understand the molecular effects of cocaine self-administration (SA), and effects of social ranking on cocaine vulnerability and treatment outcomes in male and female monkeys. Thus, we propose two Specific Aims: I. To characterize NDEs associated with cocaine SA in socially housed male and female monkeys. II. To characterize NDEs associated with success or failure of pharmacological agents to decrease cocaine SA in socially housed male and female monkeys. Our results will significantly advance progress toward characterization of non-invasive biomarkers for molecular understanding of cocaine abuse vulnerability and relapse, and contribute in developing a personalized-medicine strategy for treating drug abuse.

项目概要/摘要 可卡因使用障碍（CUD）仍然是美国的一个主要公共卫生和社会问题。一个 CUD 的特点是脆弱性、复发和治疗效果的个体差异。我们的总体目标是 更好地理解强化的长期后果中的个体差异 使用独特的非人类灵长类动物 CUD 模型研究可卡因的影响。我们建议使用神经元衍生的 血液中的外泌体（NDE）可识别与个体易感性相关的分子生物标志物 可卡因滥用、戒断后复发的可能性以及靶向治疗的成功或失败 可卡因滥用。外泌体是所有细胞类型都会释放的纳米囊泡。那些由细胞释放的 应激或病理状态与正常生理条件下释放的状态不同。服用 利用这种差异，一些基于外泌体的诊断和预后生物标志物已被 开发成功。最近的研究还表明，生物体液中的外泌体可用于建立 与甲基苯丙胺、海洛因和酒精滥用相关的分子特征。然而，外泌体具有 未用于了解可卡因滥用——此应用程序的重点。拟议的研究利用了 及时有机会使用 NIDA 资助的正在进行的研究中的血浆样本（R01 DA017763-11；PI： Nader）了解社会饲养的雌性和雄性猴子中的可卡因滥用情况。家长研究正在测试 几种药物的功效被认为对主导和从属女性的作用不同 和雄性猴子。所有猴子（社会居住并自然形成主导和从属等级制度） 正在接受全面的行为和认知测试，以及中枢多巴胺 D2/D3 的神经影像学检查 使用正电子发射断层扫描 (PET) 成像检测受体 (D2/D3R) 的可用性。随着关键成本 现有资金涵盖的措施中，这些猴子的血浆样本的可用性提供了 宝贵且具有成本效益的机会，可以增进我们对外泌体如何提供非 侵入性分子工具，让我们了解可卡因滥用和治疗结果。试点和可行性数据（a） validate our ability to isolate and characterize NDEs from stored plasma samples, and (b) support the utility of NDE 生物标记物可了解可卡因自我给药 (SA) 的分子效应以及社会影响 雄性和雌性猴子的可卡因脆弱性和治疗结果排名。因此，我们提出两个 具体目标： I. 描述社会安置的男性和女性中与可卡因 SA 相关的濒死体验的特征 猴子。二.描述与药物成功或失败相关的濒死体验 可卡因 SA 在社会饲养的雄性和雌性猴子中。我们的成果将显着推进进展 对非侵入性生物标志物进行表征，以从分子角度理解可卡因滥用脆弱性 和复发，并为制定治疗药物滥用的个性化医疗策略做出贡献。