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: 8652965
• 负责人: Prasun K Datta
• 金额: $ 30.5万
• 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/8652965
• 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.

相当大比例的艾滋病毒感染者会出现认知/运动障碍，包括周围神经病和艾滋病痴呆症。有趣的是，滥用鸦片类药物会增加艾滋病毒脑炎的频率和严重性。在HIV脑炎患者的脑组织中，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，并伴随着星形胶质细胞谷氨酸转运体EAAT2的下调。脑内星形胶质细胞EAAT2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EAAT2调节失调的机制尚不清楚。这些研究旨在阐明IL-1B和吗啡介导的EAAT2调节失调的机制。其具体目的是：1：验证IL-1B/TNF-a抑制EAAT2启动子的假设：吗啡参与NFkB激活和染色质重塑；2：验证IL-1B/TNF-a和吗啡诱导的miR-146a表达依赖于NFkB和mU阿片受体(MOR)的假设；3：验证HDAC抑制剂萝卜硫醚(SFN)改善IL-1B/TNF-a和吗啡介导的抑制EAAT2表达的假设。这些研究的结果有望对我们理解表观基因组学在EAAT2调控中的作用产生积极影响，并为使用SFN上调EAAT2表达的营养方法铺平道路，不仅在神经艾滋病中，而且在其他IL-1B/TNF-a：介导的神经退行性疾病中也是如此。