Impacts of morphine and HIV-Tat exposures and dimethylfumarate treatment on brain BDNF and mitochondrial and behavioral dysfunction.

吗啡和 HIV-Tat 暴露以及富马酸二甲酯治疗对大脑 BDNF 以及线粒体和行为功能障碍的影响。

• 批准号: 10619675
• 负责人: Marc J Kaufman
• 金额: $ 69.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619675
• 关键词: Address; Affect; Animal Behavior; Animal Model; Animals; Antioxidants; Anxiety; Applied Research; Attenuated; Autopsy; Basic Science; Behavior; Behavioral; Biogenesis; Brain; Brain-Derived Neurotrophic Factor; Cells; Cognition; Cognitive; Corpus striatum structure; Data; Development; Doxycycline; Epidemic; Exposure to; Extinction; Fumarates; Functional disorder; Future; Genetic Complementation Test; Genetic Transcription; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Hand; Health; Human; Impaired health; Impairment; In Vitro; Individual; Intervention; Knowledge; Learning; Macaca; Magnetic Resonance Spectroscopy; Memory; Mental Health; Mitochondria; Mitochondrial Proteins; Molecular Abnormality; Moods; Morphine; Morphine Dependence; Mus; NF-E2-related factor 2; NGFR Protein; Neurons; Opioid; Oral; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Phosphocreatine; Phosphorus; Play; Proteins; Reporting; Research Project Grants; Risk; SIV; Sampling; Self Administration; Severities; Signal Transduction; Structure; Substance abuse problem; Testing; Trans-Activators; Transcription Coactivator; Transgenes; Transgenic Organisms; United States National Institutes of Health; Viral; Viral Proteins; Virus Replication; Vulnerable Populations; Western Blotting; Withdrawal; Withdrawal Symptom; antiretroviral therapy; behavior test; behavioral impairment; brain dysfunction; brain metabolism; brain-derived neurotrophic factor precursor; comorbidity; flexibility; frontal lobe; improved; in vivo; innovation; inorganic phosphate; insight; nanoparticle; nanoparticle delivery; neurocognitive disorder; novel; novel therapeutics; nrf1 protein; nuclear respiratory factor; object recognition; opioid use; opioid use disorder; overdose death; physical conditioning; preference; programs; protein expression; psychostimulant; synaptogenesis; tat Protein; theories

Summary/Abstract More than 75,000 drug overdose deaths this past year were associated with opioids. To address this epidemic, NIH has prioritized the development of more effective opioid use disorder (OUD) treatments, as current interventions are helpful but inadequate. OUD is common among people living with Human Immunodeficiency Virus (HIV) and comorbid OUD/HIV increases risk for mental and physical health impairments of greater severities. Thus, comorbid OUD/HIV patients constitute a vulnerable group and basic research must study factors relevant to this group. We and others have data indicating that when combined, opioids and HIV proteins induce convergent deleterious effects that likely engender problematic opioid use behaviors and impair general health. This basic science R01 program aims to fill knowledge gaps in the individual and combined effects of the prototypical opioid, morphine, and HIV transactivator of transcription (Tat) protein, on mitochondrial function, brain derived neurotrophic factor (BDNF) expression, and on animal behavior, including those analogous to human behaviors that moderate health outcomes in patients with OUD and comorbid OUD/HIV. Improving our understanding of Tat protein’s effects is critical to better understanding effects of HIV because despite nearly complete viral suppression during antiretroviral therapy for HIV (ART), Tat is detectible with repeat testing in 40% of ART-treated patients at least once over the course of a year. This is important because Tat expression in animals induces phenotypes analogous to those observed in people living with HIV, including impairments in anxiety, inhibitory control, and brain structural and functional deficits. Tat’s relevance to comorbid OUD/HIV is illustrated in our pilot behavioral data indicating that Tat amplifies morphine taking, seeking, and post-extinction reinstatement. We also test effects of dimethylfumarate (DMF), which we have shown moderates morphine withdrawal symptoms. Studies in SIV-infected macaques report that DMF protects mitochondria and other studies show that DMF stimulates BDNF signaling. We focus on mitochondria because they supply most of the energy needed for neuronal and higher order brain function and they are impaired by morphine, Tat, and in human brain in vivo in people with OUD or HIV. Our working hypothesis is that morphine, Tat, and their combination will increase morphine self-administration, impair learning, memory, and cognitive flexibility, impair in vivo brain mitochondrial function assessed with phosphorus (31P) magnetic resonance spectroscopy, and will lower levels of mitochondrial biogenesis factors including Nuclear Respiratory Factor 1 and 2 expression, as determined postmortem. DMF, by protecting mitochondria and by increasing BDNF levels, will limit morphine’s and Tat’s deleterious effects. This basic science program aims to fill important knowledge gaps on the individual and combined effects of opioids, Tat, and DMF, and could yield data that support applied studies of novel treatments for OUD and HIV studied by us and by others, including DMF.

摘要/摘要 去年，超过75,000例药物过量死亡与阿片类药物有关。为了解决这种流行病 NIH已优先考虑更有效的阿片类药物使用障碍（OUD）治疗，因为 干预措施很有帮助，但不足。 OUD在患有人类免疫缺陷的人中很常见 病毒（艾滋病毒）和合并症/艾滋病毒增加了更大的心理和身体健康障碍的风险 严重性。这是一个合并的OUD/HIV患者构成一个脆弱的组，基础研究必须研究 与该组相关的因素。我们和其他人的数据表明，当组合时，阿片类药物和艾滋病毒 蛋白质会引起收敛的有害作用，可能会导致有问题的阿片类药物使用行为和 损害一般健康。该基础科学R01计划旨在填补个人的知识空白和 典型的阿片类药物，吗啡和HIV反式激活蛋白（TAT）蛋白的结合作用，对 线粒体功能，脑衍生的神经营养因子（BDNF）表达，以及动物行为，包括 那些类似于人类行为的人，这些行为适度了OUD和合并症患者的健康状况 Oud/HIV。提高我们对TAT蛋白效应的理解对于更好地了解艾滋病毒的影响至关重要 因为在抗逆转录病毒疗法的艾滋病毒（ART）期间绝望地几乎完全抑制病毒抑制，因此可以检测到TAT 在一年中，至少在40％的ART治疗患者中重复测试一次。这很重要 因为动物中的TAT表达会影响与艾滋病毒患者相似的表型，所以 包括动画，抑制性控制以及大脑结构和功能缺陷的损害。塔特的相关性 在我们的飞行员行为数据中说明了对合并症/艾滋病毒的介绍 寻求和恢复后的延期。我们还测试了二甲基甲酸二甲酯（DMF）的作用， 显示现代化的吗啡戒断症状。在SIV感染的猕猴报告中报告DMF保护 线粒体和其他研究表明，DMF刺激BDNF信号传导。我们专注于线粒体，因为 他们提供神经元和高阶脑功能所需的大部分能量，并受到损害 OUD或HIV患者的吗啡，TAT和人体的人体脑。我们的工作假设是吗啡， TAT及其组合将增加吗啡自我给药，损害学习，记忆和认知 灵活性，通过磷（31p）磁共振评估的体内脑线粒体功能受损 光谱法，并将降低线粒体生物发生因子的水平，包括核呼吸因子1 和2表达，如验尸后确定。 DMF，通过保护线粒体并增加BDNF 水平将限制吗啡和Tat的有害影响。这个基础科学计划旨在填补重要的 关于阿片类药物，TAT和DMF的个体和联合影响的知识差距，可以产生数据 支持我们和其他人（包括DMF）对OUD和HIV研究的新型治疗的支持。