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.
There is growing evidence that HIV-1 induced the pro-inflammatory cytokines IL-1B and TNF-a play significant detrimental role in NeuroAIDS. Furthermore, drugs of abuse such as heroin and its metabolite morphine in such scenario can worsen progression and treatment response. Elucidation of the effects of pro-inflammatory cytokines and drugs of abuse on brain structure and function can open new avenues in the therapy of neuronal dysfunction and death.
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