A new pathway of spinal neurons in neuropathic pain induced by HIV with opioid

脊髓神经元在 HIV 和阿片类药物诱导的神经性疼痛中的新通路

基本信息

批准号：
10454144
负责人：
SHUANGLIN HAO
金额：
$ 34.54万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454144
关键词：
Address American Applications Grants Area Binding Biological Assay Bromodomain Capsid Proteins Cells Chromatin Chronic Clinical Data Complication Data Deacetylase Development Drug Metabolic Detoxication Economics Enhancers Epidemic Epigenetic Process Functional disorder Gene Expression Genes Genetic Transcription HIV HIV Envelope Protein gp120 HIV Infections HIV neuropathy HIV-1 Health Heroin Histone H3 Human Image Immune Impairment Individual Knockout Mice Link Longevity Mediating Mitochondria Modeling Molecular Morphine National Institute of Drug Abuse Nervous System Physiology Neuraxis Neuroglia Neurologic Neurologic Deficit Neurons Opioid Opioid Analgesics Oxidative Stress Pain Painless Pathway interactions Patients Pharmacology Play Production Protein Family Public Health Reader Research Research Personnel Research Project Grants Role Severities Signal Transduction Signal Transduction Pathway Sirtuins Societies Spinal cord posterior horn Superoxides System TNF gene Testing Therapeutic Intervention United States Up-Regulation Viral Vector Virus Diseases antiretroviral therapy base c-myc Genes chronic pain conditional knockout cytokine drug of abuse economic cost global health histone methylation in vivo insight interest mechanical allodynia neuroinflammation neuron loss neuronal circuitry neurotoxic neurotoxicity neurotransmission novel novel therapeutics opioid abuse opioid epidemic opioid overuse painful neuropathy promoter receptor response spinal pathway transcription factor

项目摘要

Project Summary: In response to the RFA-MH-18-610---“the FOA invites research grant applications to decipher pathways and mechanisms responsible for HIV-1 induced central nervous system (CNS) dysfunction”, we focused on the Areas of Research Interest: “NIDA is interested in understanding the underlying mechanisms whereby drugs of abuse and HIV infection interact to impair CNS functions mediated through altered neuronal circuits, neuronal receptors.” The United States currently has an opioid overuse epidemic. Despite the advent of effective anti-retroviral therapy, HIV-neuropathic pain (HIV-NP) is a common neurological complication as patients enjoy longer life spans. This serious health issue is further exacerbated by chronic abuse of opiates often seen in HIV+ individuals, leading, in turn, to increased severity of neurological deficits. HIV and chronic morphine use/abuse can increase cytokine production resulting in enhanced neuroinflammation. HIV-related neuron damage is induced either directly by neurotoxic substances or indirectly by activating glial cells releasing neurotoxic factors (such as, TNFα). Our preliminary data shows that repeated exposure of HIV coat protein gp120 with morphine decreased neuronal sirtuin (SIRT) 3 expression, an NAD+-dependent deacetylase that regulates mitochondrial detoxification in the spinal cord dorsal horn (SCDH), and increased in neuronal mitochondrial superoxide. However, the exact upstream pathways responsible for the loss of neuronal SIRT3 in the SCDH in the interaction of gp120 and morphine is not clear. Recent studies show that the epigenetic reader Brd4, one of bromodomain and extraterminal (BET) family of proteins modulates, the expression of transcriptional factor c-Myc. The epigenetic writer, enhancer of zeste homology 2 (EZH2) suppresses gene expression via histone methylation (e.g., H3K27me3). Brd4 positively regulates EZH2 transcription through upregulation of c-Myc. In this proposal we will test the hypothesis that neuronal TNFRI- --Brd4---c-Myc---EZH2 epigenetic pathway mediates the loss of anti-oxidative SIRT3 system in the spinal cord dorsal horn in HIV/chronic opioid-related neuropathic pain. We will combine molecular and epigenetic approach, knockout (KO) mice, conditional knockout (cKO) mice, neuron-selective viral vectors, mitochondrial superoxide imaging, and molecular-pharmacological assays all in vivo to prove novel mechanisms. Based on the neuronal signal transduction pathway, the results of these studies will provide insights on the treatment of neuropathic pain of the interaction of HIV and opioids.

项目摘要：为了响应RFA-MH-18-610 ---“ FOA邀请研究赠款申请，负责HIV-1诱导中枢神经系统（CNS）功能障碍的机制”，我们专注于研究领域感兴趣的领域：“ NIDA有兴趣了解基本机制滥用和艾滋病毒感染的药物相互作用，以损害通过改变神经元电路介导的CNS功能，神经元接收者。有效的抗逆转录病毒疗法，HIV - 神经性疼痛（HIV-NP）是常见的神经系统并发症患者享受更长的寿命。长期滥用选择，这一严重的健康问题进一步加剧了经常在艾滋病毒+个体中看到，导致神经系统缺陷的严重程度增加。艾滋病毒和慢性吗啡使用/滥用会增加细胞因子的产生，从而增加神经炎症。与艾滋病毒有关神经元损伤是通过神经毒性物质直接诱导的，或通过激活神经胶质细胞而诱导的释放神经毒性因子（例如TNFα）。我们的初步数据表明，艾滋病毒涂层反复暴露蛋白质GP120带有吗啡改善神经元SIRTUIN（SIRT）3表达，nad+依赖性脱乙酰基酶调节脊髓背角（SCDH）中的线粒体排毒并增加在神经元线粒体超氧化物中。但是，确切的上游途径负责损失 GP120和吗啡相互作用中SCDH中的神经元SIRT3尚不清楚。最近的研究表明表观遗传学读取器BRD4，溴结构域和外部（BET）蛋白质家族之一，该家族调节转录因子C-MYC的表达。表观遗传作者，Zeste同源性2（EZH2）的增强剂通过组蛋白甲基化抑制基因表达（例如H3K27Me3）。 BRD4积极调节EZH2 通过上调C-MYC的转录。在此提案中，我们将检验以下假设。 -brd4 --- c-Myc --- EZH2表观遗传途径介导脊柱中抗氧化SIRT3系统的损失艾滋病毒/慢性阿片类药物相关的神经性疼痛中的脐带背角。我们将结合分子和表观遗传学进近，敲除（KO）小鼠，有条件的敲除（CKO）小鼠，神经选择性病毒载体，线粒体超氧化物成像和分子 - 药理学分析均在体内证明新颖机制。基于神经元信号转移途径，这些研究的结果将提供关于治疗HIV和阿片类药物相互作用的神经性疼痛的见解。