Role of epigenetics in glutamate transporter EAAT2regulation in neuroaids

表观遗传学在神经辅助谷氨酸转运蛋白 EAAT2 调节中的作用

• 批准号: 8140874
• 负责人: Prasun K Datta
• 金额: $ 31.12万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140874
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Astrocytes; Behavioral; Brain; Brain Injuries; Cessation of life; Clinical; Cognitive; DNA Methylation; Data; Dementia; Down-Regulation; Epigenetic Process; Feasibility Studies; Frequencies; Functional disorder; Glutamate Transporter; Glutamates; Goals; HIV; HIV Infections; HIV encephalitis; HIV-1; Heroin; Hippocampus (Brain); Histone Deacetylase Inhibitor; Human; Incidence; Individual; Inflammation; Inflammatory; Literature; Mediating; MicroRNAs; Microglia; Molecular; Morphine; Mus; NF-kappa B; Nervous system structure; Neurodegenerative Disorders; Neuronal Dysfunction; Nutraceutical; Opiates; Outcome Study; Patients; Peripheral Nervous System Diseases; Play; Rattus; Regulation; Repression; Research; Role; Severities; Signal Transduction; Slice; Structure; Sulforaphane; TNF gene; Testing; Work; base; brain tissue; chromatin remodeling; cytokine; design; drug abuser; drug of abuse; epigenomics; excitotoxicity; extracellular; fetal; histone modification; macrophage; motor disorder; mu opioid receptors; nervous system disorder; neurotoxicity; novel therapeutic intervention; prevent; promoter; treatment response

A significant proportion of patients infected with HIV develop cognitive/motor disorders including peripheral neuropathies and AIDS dementia. Interestingly, drugs of abuse such as opiates increase the frequency and severity of HIV encephalitis. In brain tissues of patients with HIV encephalitis, IL-1B and TNF-a: expression is increased in infiltrating macrophages, microglia and astrocytes with concomitant down regulation of astroglial glutamate transporter, EAAT2. Dysregulation of astroglial EAAT2 in the brain leads to glutamate mediated neurotoxicity (also known as excitotoxicity). However, the mechanism of dysregulation of EAAT2 by IL-1B/TNF-a: and morphine are unknown. The studies proposed are designed to elucidate the mechanism of IL-1B and morphine mediated dysregulation of EAAT2. The specific aims are 1: To test the hypothesis that EAAT2 promoter repression by IL-1B/TNF-a: and morphine involves activation of NFkB and chromatin remodeling, 2: To test the hypothesis that IL-1B/TNF-a and morphine induced miR-146a expression is NFkB and ¿mu¿-opioid receptor (MOR) dependent, and 3: To test the hypothesis that HDAC inhibitor, Sulforaphane (SFN) ameliorates IL-1B/TNF-a: and morphine mediated repression of EAAT2 expression. The outcomes of these studies are expected to have a positive impact in our understanding of the role of epigenomics in EAAT2 regulation and pave the way to a nutraceutical approach using SFN to upregulate EAAT2 expression not only in NeuroAIDS but also in other IL-1B/TNF-a: mediated neurodegenerative diseases.

很大一部分感染艾滋病毒的病人会出现认知/运动障碍，包括周围神经病变和艾滋病痴呆。有趣的是，阿片类药物等滥用药物增加了艾滋病毒脑炎的频率和严重程度。在患有HIV脑炎的患者的脑组织中，IL-1B和TNF-α：在浸润性巨噬细胞、小胶质细胞和星形胶质细胞中表达增加，伴随着星形胶质细胞谷氨酸转运蛋白EAAT 2的下调。脑中星形胶质细胞EAAT 2的失调导致谷氨酸介导的神经毒性（也称为兴奋性毒性）。然而，IL-1B/TNF-α和吗啡对EAAT 2的失调机制尚不清楚。 本研究旨在阐明IL-1B和吗啡介导的EAAT 2失调的机制。具体目标是1：为了检验IL-1B/TNF-α和吗啡对EAAT 2启动子的抑制涉及NF κ B的活化和染色质重塑的假设，2：为了检验IL-1B/TNF-α和吗啡诱导的miR-146 a表达是NF κ B和μ-阿片受体（莫尔）依赖性的假设，和3：为了检验HDAC抑制剂萝卜硫素（SFN）改善IL-1B/TNF-α的假设：和吗啡介导的EAAT 2表达的抑制。 这些研究的结果有望对我们理解表观基因组学在EAAT 2调控中的作用产生积极影响，并为使用SFN上调EAAT 2表达的营养方法铺平道路，不仅在NeuroAIDS中，而且在其他IL-1B/TNF-a介导的神经退行性疾病中。