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.

在感染HIV的患者中，很大一部分患者发展了认知/运动障碍，包括周围神经病和艾滋病痴呆症。有趣的是，诸如滥用药物（例如扩大HIV脑炎的频率和严重程度）。在HIV脑炎患者的脑组织中，IL-1B和TNF-A：表达在浸润巨噬细胞，小胶质细胞和星形胶质细胞中增加，同时减少了星形胶质酸谷氨酸转运蛋白的调节EAAT2。大脑中星形胶质细胞EAAT2的失调会导致谷氨酸介导的神经毒性（也称为兴奋性毒性）。但是，IL-1B/TNF-A和吗啡的EAAT2失调机制尚不清楚。提出的研究旨在阐明IL-1B和吗啡介导的EAAT2失调的机理。具体目的是1：测试以下假说：EAAT2启动子通过IL-1B/TNF-A：抑制抑制吗啡涉及激活NFKB和染色质的重塑，2：测试IL-1B/TNF-A和吗啡诱导的miR-146a表达是NFKB和nfkb和3 ipothing oftord andoth andoth andosoth andopose andoshosore andophosity andophosity and opii iciiii，（sypo） HDAC抑制剂Sulforaphane（SFN）可以改善IL-1B/TNF-A：吗啡介导的EAAT2表达的表达。预计这些研究的结果将对我们对表观基因组学在EAAT2调节中的作用的理解产生积极影响，并使用SFN使用SFN铺平了采用营养方法的方式，不仅在神经辅助中更新EAAT2表达，而且在其他IL-1B/TNF-A中也更新了EAAT2的表达。