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

基本信息

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
项目类别：
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

项目摘要

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.

相当一部分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，阿片类药物等滥用药物会增加艾滋病毒脑炎、IL-1B 和脑组织中艾滋病毒脑炎的发生频率和严重程度。 TNF-a：在浸润巨噬细胞、小胶质细胞和星形胶质细胞中表达增加，同时星形胶质细胞谷氨酸转运蛋白 EAAT2 失调。大脑中的星形胶质细胞 EAAT2 会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-a 和吗啡对 EAAT2 的失调机制尚不清楚。所提出的研究旨在阐明 IL 的机制。 -1B 和吗啡介导的 EAAT2 失调具体目标是 1：检验 EAAT2 启动子抑制的假设。 IL-1B/TNF-a：和吗啡涉及 NFkB 激活和染色质重塑，2：检验 IL-1B/TNF-a 和吗啡诱导 miR-146a 表达是 NFkB 和 ¿亩-阿片受体 (MOR) 依赖性，以及 3：检验 HDAC 抑制剂萝卜硫素 (SFN) 改善 IL-1B/TNF-a 和吗啡介导的 EAAT2 表达抑制的假设。这些研究的结果预计将有一个结果。这对我们理解表观基因组学在 EAAT2 调节中的作用产生了积极影响，并为使用 SFN 上调 EAAT2 表达的营养保健方法铺平了道路不仅在 NeuroAIDS 中，而且在其他 IL-1B/TNF-a 介导的神经退行性疾病中也有作用。