Mechanisms underlying prescription opioid use post social defeat in HIV+ adolescents

HIV 青少年社交失败后处方阿片类药物使用的潜在机制

• 批准号: 10700525
• 负责人: Gurudutt N Pendyala
• 金额: $ 25.93万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700525
• 关键词: Address; Adolescence; Adolescent; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Architecture; Attitude; Behavior; Behavioral; Biogenesis; Biological Markers; Brain; Catecholamines; Cell physiology; Cells; Cognitive; Collaborations; Coupled; Data; Dendritic Spines; Development; Disease; Drug Delivery Systems; Emotional; Exposure to; Functional disorder; Funding Mechanisms; Future; Glean; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; HIV; HIV Infections; HIV-infected adolescents; Human; Incidence; Individual; Inflammation; Injury; Knowledge; Lead; Lipids; Literature; Measures; Mental disorders; Molecular; Neurological outcome; Neurons; Outcome; Oxycodone; Pathway interactions; Personal Satisfaction; Pharmaceutical Preparations; Phase; Plasma; Pre-Clinical Model; Prejudice; Proteins; Proteomics; Psychopathology; Psychosocial Stress; RNA; Rat Transgene; Rattus; Reporting; Research; Research Personnel; Risk; Role; Self Administration; Severities; Social Development; Societies; Stress; Substance abuse problem; Synapses; Testing; Therapeutic; Tissues; Translating; Untranslated RNA; Validation; Vulnerable Populations; Work; addiction; bullying; confocal imaging; critical developmental period; disorder risk; emerging adult; experience; extracellular vesicles; improved; intravenous drug use; nanocarrier; nanoplasmonic; neural; next generation; novel; novel marker; novel therapeutics; opioid use; prescription opioid; preventive intervention; protein biomarkers; social; social defeat; social stigma; social stress; social vulnerability; synaptic function; treatment group

Abstract From a developmental milestone, adolescence is a very critical phase since there are a plethora of changes occurring on different tiers - physical, cognitive, emotional, social, and behavioral. Any negative experiences at this critical developmental period can significantly impact the outcomes with serious ramifications that could persist into adulthood. This problem is further aggravated in HIV+ adolescents due to the associated stigma, negative attitudes, and prejudice in society. Social defeat (SD) employing a resident-intruder paradigm mimics bullying in humans and is considered a relevant animal model of psychosocial stress in defeated individuals. While previous literature has reported the experience of social stress to correlate with a higher incidence of stress-related psychiatric and addictive disorders, molecular mechanisms contributing to these outcomes still remain unclear. Our goal is on discerning molecular mechanisms and focuses on decoding the role of extracellular vesicles (EV) in exacerbating synaptic function and precipitating prescription opioid use in HIV+ adolescents post SD. Our preliminary studies using a preclinical model: HIV transgenic rats have revealed alterations in brain derived EV (BDEV) sizes with HIV infection. Based on this premise, our overarching central hypothesis is SD in HIV+ adolescent rats further exacerbate BDEV dynamics that aggravate synaptic injury and precipitates prescription opioid use. Under Aim 1, we seek to elucidate if SD in HIV+ adolescent rats dysregulate dynamics of BDEV biogenesis and increases vulnerability to prescription opioid use. In Aim 2 we will delineate mechanisms associated with adolescent HIV+ BDEVs post SD elicit higher inflammation and exacerbate synaptic injury. Upon completion of these goals, we expect to significantly enhance our knowledge of the role of BDEVs to regulate brain function post SD in HIV+ adolescents and identification of novel BDEV protein markers. Such information gleaned will further fuel mechanistic studies and eventually help develop future strategies to treat and improve neurological outcomes in this vulnerable population.

抽象的 从发展里程碑来看，青春期是一个非常关键的阶段，因为有太多的变化 发生在不同的层面——身体、认知、情感、社交和行为。任何负面经历 这一关键的发展时期可能会对结果产生重大影响，从而产生严重后果 坚持到成年。由于相关的耻辱，这个问题在艾滋病毒+青少年中进一步加剧， 社会上的消极态度和偏见。采用居民-入侵者范式模仿的社会失败（SD） 人类欺凌被认为是受挫个体心理社会压力的相关动物模型。 虽然之前的文献报道了社会压力的经历与较高的发病率相关 与压力相关的精神疾病和成瘾性疾病，导致这些结果的分子机制仍然 仍不清楚。我们的目标是辨别分子机制，并重点解码其作用 细胞外囊泡 (EV) 会加剧 HIV+ 患者的突触功能并促使处方阿片类药物的使用 SD 后的青少年。我们使用临床前模型进行的初步研究：HIV 转基因大鼠揭示了 HIV 感染导致脑源性 EV（BDEV）大小发生变化。基于这个前提，我们的总体中心 假设 HIV+ 青春期大鼠中的 SD 进一步加剧 BDEV 动态，从而加剧突触损伤 促使处方阿片类药物的使用。在目标 1 下，我们试图阐明 HIV+ 青春期大鼠的 SD 是否失调 BDEV 生物发生的动态并增加处方阿片类药物使用的脆弱性。在目标 2 中，我们将描绘 SD 后与青少年 HIV+ BDEV 相关的机制会引起更高的炎症并加剧 突触损伤。完成这些目标后，我们预计将显着增强我们对以下角色的了解： BDEV 在 HIV+ 青少年 SD 后调节脑功能并鉴定新型 BDEV 蛋白标记物。 收集到的此类信息将进一步推动机制研究，并最终有助于制定未来的战略 治疗和改善这一弱势群体的神经系统结果。