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 去年有超过75，000例药物过量死亡与阿片类药物有关。为了应对这一流行病， NIH优先考虑开发更有效的阿片类药物使用障碍（OUD）治疗， 干预是有益的，但不够。OUD在人类免疫缺陷患者中很常见 病毒（HIV）和OUD/HIV共病使精神和身体健康损害的风险增加 严重性因此，OUD/HIV共病患者构成了一个弱势群体，必须进行基础研究 与这个群体有关的因素。我们和其他人的数据表明，阿片类药物和艾滋病毒结合使用时， 蛋白质诱导可能产生问题阿片类药物使用行为的会聚性有害作用， 损害一般健康。这个基础科学R 01计划旨在填补个人的知识空白， 原型阿片样物质、吗啡和HIV转录反式激活因子（达特）蛋白的联合作用， 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，在OUD和共病患者中调节健康结果 OUD/艾滋病毒。提高我们对达特蛋白作用的理解对于更好地理解艾滋病毒的作用至关重要 因为尽管在抗逆转录病毒疗法（ART）中几乎完全抑制了病毒，但达特仍是可检测的 40%的ART治疗患者在一年内至少重复检测一次。这很重要 因为动物中的达特表达诱导的表型类似于在HIV携带者中观察到的表型， 包括焦虑、抑制控制和大脑结构和功能缺陷的损伤。达特的相关性 在我们的试验性行为数据中显示，达特放大了吗啡的服用， 寻求和灭绝后的恢复。我们还测试了富马酸二甲酯（DMF）的影响，我们已经 表现出中度吗啡戒断症状在SIV感染的猕猴中进行的研究报告称，DMF可保护 线粒体和其他研究表明，DMF刺激BDNF信号传导。我们关注线粒体是因为 它们提供神经元和高级脑功能所需的大部分能量， 吗啡、达特和OUD或HIV患者体内的人脑中。我们假设吗啡， 达特，以及它们的组合将增加吗啡的自我施用，损害学习、记忆和认知能力。 灵活性，受损在体内脑线粒体功能评估与磷（31 P）磁共振 光谱，并将降低线粒体生物合成因子的水平，包括核呼吸因子1 和2表达，如死后确定的。DMF，通过保护线粒体和增加BDNF 水平，将限制吗啡和达特的有害影响。这个基础科学计划旨在填补重要的 关于阿片类药物、达特和DMF的单独和联合作用的知识差距，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。