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.

项目摘要/摘要 在美国，可卡因使用障碍（CUD）仍然是主要的公共卫生和社会问题。一个 CUD的标志是脆弱性，缓解和治疗效率的个体差异。我们的总体目标是 在增强的长期后果中更好地了解个体差异 使用独特的非人类私人模型可卡因的影响。我们建议使用神经元衍生 血液中的外泌体（NDE），以识别与个人脆弱性相关的分子生物标志物 可卡因滥用，禁欲后接力的敏感性以及目标疗法的成功或失败 可卡因滥用。外泌体是所有细胞类型释放的纳米宇宙。那些由细胞释放的 压力或病理状态与在正常生理条件下释放的状态不同。服用 这种差异的优点，几个基于外泌体的诊断和预后生物标志物已经是 成功发展。最近的研究还表明，生物流体中的外泌体可用于建立 与甲基苯丙胺，海洛因和酗酒有关的分子特征。但是，外泌体具有 没有被用来了解可卡因滥用 - 该应用程序的重点。拟议的研究大写 及时使用NIDA资助研究的血浆样品（R01 DA017763-11; PI： 纳德（Nader））了解在社会住所的女性和男性猴子中可卡因滥用。家长研究正在测试 几种被认为在主要女性和下属女性中起作用的药物的效率不同 和雄猴。所有猴子（在社会上且自然形成占主导地位和下属层次结构） 正在进行全面的行为和认知测试，以及中央多巴胺D2/D3的神经影像学 使用正电子发射断层扫描（PET）成像的受体（D2/D3R）可用性。用密钥的费用 现有资金涵盖的措施，这些猴子的血浆样本的可用性提供了 有价值且具有成本效益的机会，以促进我们对外泌体如何提供非 - 侵入性分子工具，以告知我们有关可卡因滥用和治疗结果。飞行员和可行性数据（a） 验证我们从储存的等离子样品中分离和表征NDE的能力，（b）支持 NDE生物标志物了解可卡因自我管理（SA）的分子效应以及社会的影响 在男性和雌性猴子的可卡因脆弱性和治疗结果上排名。那我们提出了两个 具体目的：I。以社交男性和女性的可卡因SA相关的NDE来表征 猴子。 ii。表征与药物成功或失败相关的NDE 可卡因SA在社会住所的男性和雌性猴子中。我们的结果将大大提高进度 旨在表征非侵入性生物标志物，以分子理解可卡因滥用脆弱性 和继电器，并为制定一种个性化医学策略来治疗药物滥用。