Role of epigenetics in glutamate transporter EAAT2regulation in neuroaids

相当一部分感染艾滋病毒的患者会出现认知/运动障碍，包括周围神经病变和艾滋病痴呆。有趣的是，滥用药物如阿片类药物会增加艾滋病毒脑炎的频率和严重程度。在HIV脑炎患者脑组织中，浸润性巨噬细胞、小胶质细胞和星形胶质细胞中IL-1B和TNF-a：表达升高，同时星形胶质谷氨酸转运蛋白EAAT2下调。星形胶质细胞EAAT2在大脑中的失调导致谷氨酸介导的神经毒性（也称为兴奋毒性）。然而，IL-1B/TNF-a和吗啡对EAAT2的失调机制尚不清楚。本研究旨在阐明IL-1B和吗啡介导的EAAT2失调的机制。具体目的是：1 .验证IL-1B/TNF-a和吗啡抑制EAAT2启动子涉及NFkB激活和染色质重塑的假设；2 .验证IL-1B/TNF-a和吗啡诱导的miR-146a表达依赖于NFkB和MOR的假设；3 .验证HDAC抑制剂Sulforaphane （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，并为利用SFN上调EAAT2在神经aids以及其他IL-1B/TNF-a介导的神经退行性疾病中的表达铺平道路。

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.