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.

项目概要 药物滥用障碍（SUD）仍然是美国的一个大问题。 CARRS 的主要目标 中心旨在了解青春期期间的睡眠和昼夜节律特征以及环境干扰如何 导致药物滥用的脆弱性增加。我们预测生物和 环境因素导致这种风险增加。该中心项目 3 的目标是提供 在人类受试者和啮齿动物模型中进行转化研究，确定如何进行的机制细节 昼夜节律和睡眠中断会改变奖励回路。我们还将测试潜在的治疗方法 青少年的社交时差可能会降低 SUD 的风险。在这里我们将使用一种非侵入性的方法来评估 使用从毛囊收集的皮肤细胞的人体分子时钟，已针对 分子节律的测量。然而，迄今为止还没有研究培养青少年细胞进行分子生物学研究。 节律测量、与其他睡眠、奖励和昼夜节律测量相关的分子节律，或 研究了潜在治疗化合物对这些节律的影响。在项目 3 中我们将利用 在 P1/2 中从人类受试者中收集毛囊样本，并将这些数据与彻底的节奏相结合， 这些项目中收集的睡眠、认知和奖励数据。我们还将确定如何进行分子测量 啮齿类动物的行为与 P4/5 中收集的电生理数据相关。此外，我们正在测试 对分子节律的潜在药物干预将为未来的临床试验提供信息。我们也是 使用啮齿类动物提供感兴趣的大脑区域中详细的基因和蛋白质表达，以响应特定的 睡眠和昼夜节律的操纵。我们要回答的问题是：（1）睡眠和睡眠状况如何？ 昼夜节律表型和成瘾脆弱性与分子节律相关？这将在两个方面进行测试 通过细胞培养研究人类和大鼠。 (2) 昼夜节律的分子机制是什么 和睡眠中断共同或单独导致人们更容易滥用药物 青少年？这将在核心 B 中产生的啮齿动物中进行测试，这些啮齿动物经历过特定的睡眠和 在 PFC 和 NAc 中进行昼夜节律操作，然后进行 RNA 测序和蛋白质组学。 (3) 有吗 药物干预将改变和/或放大人类受试者的分子节律，这可能是 对于生物钟延迟和昼夜节律失调的青少年有用吗？这将直接在单元中进行测试 文化。总而言之，这些研究可能为有风险的青少年提供新的治疗方法 物质使用障碍。