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

• 批准号: 10217077
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217077
• 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

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.

项目总结: