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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033213-04
Application #
8652965
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Sorensen, Roger
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$305,028
Indirect Cost
$101,317
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Barrero, Carlos A; Datta, Prasun K; Sen, Satarupa et al. (2013) HIV-1 Vpr modulates macrophage metabolic pathways: a SILAC-based quantitative analysis. PLoS One 8:e68376
Regan, Patrick M; Dave, Rajnish S; Datta, Prasun K et al. (2012) Epigenetics of ýý-opioid receptors: intersection with HIV-1 infection of the central nervous system. J Cell Physiol 227:2832-41