Molecular rhythms and substance abuse vulnerability in adolescents

青少年的分子节律和药物滥用脆弱性

• 批准号: 10217072
• 负责人: Colleen A McClung
• 金额: $ 29.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217072
• 关键词: ARNTL gene; Adolescence; Adolescent; Adolescent Development; Behavior; Behavior Therapy; Behavioral; Biological Assay; Biological Factors; Brain region; Cell Culture Techniques; Cells; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Clinical; Clinical Research; Clinical Trials; Cognition; Cultured Cells; Data; Developmental Process; Electrophysiology (science); Environmental Risk Factor; Future; Gene Expression; Genetic; Goals; Hair; Hair follicle structure; Human; Impulsivity; Individual; Intervention; Jet Lag Syndrome; Lead; Light; Luciferases; Machine Learning; Measurement; Measures; Methods; Modeling; Molecular; Molecular Target; Periodicity; Pharmacology; Phase; Phenotype; Physiological; Proteomics; Protocols documentation; Rattus; Rewards; Risk; Rodent; Rodent Model; Sampling; Skin; Sleep; Sleep Fragmentations; Sleep disturbances; Substance Use Disorder; Substance abuse problem; Teenagers; Testing; Therapeutic; United States; Variant; addiction; circadian; circadian pacemaker; cognitive control; experience; human subject; interest; molecular clock; neuronal circuitry; novel; personalized medicine; protein expression; response; reward circuitry; social; social factors; substance use; substance use prevention; trait; transcriptome sequencing; translational study; vulnerable adolescent; young adult

PROJECT SUMMARY Substance use disorder (SUD) remains a large problem in the United States. The primary goal of the CARRS Center is to understand how sleep and circadian rhythm traits and environmental disruptions during adolescence lead to increased vulnerability for substance abuse. We predict that a combination of biological and environmental factors contribute to this increased risk. The goal of Project 3 in the Center is to provide translational studies in both human subjects and rodent models that determine mechanistic details of how circadian rhythm and sleep disruption alter reward circuitry. We will also test potential therapeutic treatments for social jet lag in adolescents that might mitigate risk for SUD. Here we will use a noninvasive method of assessing the human molecular clock using skin cells collected from hair follicles, which has been fully optimized for the measure of molecular rhythms. However, no study to date has cultured cells from adolescents for molecular rhythm measurement, associated molecular rhythms with other sleep, reward and circadian measures, or investigated the effects of potentially therapeutic compounds on these rhythms. In Project 3 we will be utilizing hair follicle samples collected in P1/2 from human subjects and combine this data with the thorough rhythm, sleep, cognition, and reward data collected in those projects. We will also determine how molecular measures in rodents correlate with behavioral and electrophysiological data collected in P4/5. Moreover, we are testing potential pharmacological interventions on molecular rhythms which will inform future clinical trials. We are also using rodents to provide detailed gene and protein expression in brain regions of interest in response to specific manipulations of sleep and circadian rhythms. The questions we want to answer are: (1) How are sleep and circadian rhythm phenotypes and addiction vulnerability related to molecular rhythms? This will be tested in both humans and rats through cell culture studies. (2) What are the molecular mechanisms by which circadian rhythm and sleep disruptions in combination or independently lead to increased vulnerability for substance abuse in adolescents? This will be tested in rodents generated in Core B that have experienced specific sleep and circadian manipulations followed by RNA sequencing and proteomics in PFC and NAc. (3) Are there pharmacological interventions that will shift and/or amplify molecular rhythms in human subjects that could be useful for adolescents with delayed chronotypes and circadian misalignment? This will be directly tested in cell culture. Taken together, these studies could point towards novel treatments for adolescents that are at risk for substance use disorders.

项目摘要 在美国，药物使用障碍（SUD）仍然是一个大问题。 Carrs的主要目标 中心要了解青春期睡眠和昼夜节律特征和环境破坏 导致增加滥用药物的脆弱性。我们预测生物学和 环境因素导致这种风险增加。中心项目3的目标是提供 在人类受试者和啮齿动物模型中的转化研究，以确定如何的机理细节 昼夜节律和睡眠破坏会改变奖励电路。我们还将测试潜在的治疗治疗 社交喷气式滞后的青少年可能会减轻SUD风险。在这里，我们将使用一种无​​创方法来评估 使用从毛囊中收集的皮肤细胞的人分子时钟，已完全优化 分子节律的度量。但是，迄今为止尚无研究细胞从青少年培养的细胞 节奏测量，与其他睡眠，奖励和昼夜节律措施相关的分子节奏或 研究了潜在的治疗化合物对这些节奏的影响。在项目3中，我们将使用 从人类受试者中收集的P1/2中的毛囊样品，将这些数据与彻底的节奏相结合， 在这些项目中收集的睡眠，认知和奖励数据。我们还将确定分子测量 在啮齿动物中，与P4/5中收集的行为和电生理数据相关。而且，我们正在测试 分子节律的潜在药理干预措施将为未来的临床试验提供依据。我们也是 使用啮齿动物在感兴趣的大脑区域提供详细的基因和蛋白质表达，以应对特定 睡眠和昼夜节律的操纵。我们要回答的问题是：（1）睡眠和如何 昼夜节律表型和成瘾脆弱性与分子节奏有关？这两个都将在两者中进行测试 人类和大鼠通过细胞培养研究。 （2）昼夜节律的分子机制是什么 结合睡眠中断或独立导致滥用药物滥用的脆弱性 青少年？这将在经历特定睡眠和 PFC和NAC中的RNA测序和蛋白质组学，然后进行昼夜节律操纵。 （3）在那里 可以在人类受试者中转移和/或扩大分子节律的药理干预措施可能是 对于延迟计时型和昼夜节律未对准的青少年有用吗？这将直接在单元格中进行测试 文化。综上所述，这些研究可能指向有面临风险的青少年的新颖治疗方法 物质使用障碍。