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。 NIH 优先考虑开发更有效的阿片类药物使用障碍 (OUD) 治疗方法，因为目前 OUD 在人类免疫缺陷患者中很常见，但干预措施是有帮助的。 病毒 (HIV) 和合并症 OUD/HIV 会增加更大范围的精神和身体健康损害的风险 因此，共病 OUD/HIV 患者构成了弱势群体，必须进行基础研究。 我们和其他人的数据表明，阿片类药物和艾滋病毒结合起来。 蛋白质会引起聚合有害作用，可能会导致有问题的阿片类药物使用行为， 这项基础科学 R01 计划旨在填补个人和群体的知识空白。 原型阿片类药物、吗啡和 HIV 转录反式激活蛋白 (Tat) 的综合作用， 线粒体功能、脑源性神经营养因子 (BDNF) 表达以及动物行为，包括 那些类似于人类行为的行为可以调节 OUD 和共病患者的健康结果 提高我们对 Tat 蛋白作用的了解对于更好地了解 HIV 的作用至关重要。 因为尽管 HIV 抗逆转录病毒治疗 (ART) 期间几乎完全抑制病毒，但 Tat 仍可检测到 每年至少对 40% 接受 ART 治疗的患者进行一次重复测试，这一点很重要。 因为动物中的 Tat 表达会诱导与艾滋病毒感染者中观察到的表型类似的表型， 包括焦虑、抑制控制以及大脑结构和功能缺陷的损害。 我们的试点行为数据表明 Tat 会放大吗啡的服用量， 我们还测试了我们拥有的富马酸二甲酯 (DMF) 的效果。 对感染 SIV 的猕猴进行的研究表明，DMF 可以缓解吗啡戒断症状。 线粒体和其他研究表明 DMF 刺激 BDNF 信号传导，因为我们关注线粒体。 它们提供神经和高级大脑功能所需的大部分能量，并且它们受到以下因素的损害： 吗啡、Tat 以及 OUD 或 HIV 患者体内的人脑中，我们的工作假设是吗啡、 Tat 及其组合会增加吗啡自我给药，损害学习、记忆和认知 灵活性，通过磷 (31P) 磁共振评估损害体内脑线粒体功能 光谱，并会降低线粒体生物合成因子（包括核呼吸因子 1）的水平 和 2 的表达，根据死后 DMF 的测定，通过保护线粒体和增加 BDNF 来实现。 水平，将限制吗啡和 Tat 的有害影响。该基础科学计划旨在填补重要的空白。 关于阿片类药物、Tat 和 DMF 的单独影响和综合影响的知识差距，并可能产生以下数据： 支持我们和其他人（包括 DMF）研究的 OUD 和 HIV 新疗法的应用研究。