A major complication in the progression of AIDS is the development of neurodegeneration that is caused in part by the viral protein gp120. Interactions between gpl20 and glia are believed to trigger chemokine signaling cascades that result in secretion of neurotoxins. This chemoldne signaling cascade is secondary to stimulation of chemokine receptors by gp120. Recent studies have demonstrated that ethanol is able to suppress the neurodegeneration caused by gp120; however, the mechanisms of this neuroprotection are unclear. Therefore, the purpose of this study is to clarify the effects of ethanol in regards to gp120- induced neuronal injury. The hypothesis is that ethanol is able to disrupt chemoldne signaling in microglia, reducing the damage from gp120. To address this hypothesis, chemokine signaling events such as neurotoxin release from microglia will be examined after gpl20 and chemokine stimulation, as well as these effects after ethanol pretreatment. The specific alterations that occur in microglia in response to ethanol will also be studied.
Aim I is: To determine whether ethanol disrupts the CXCR4 endogenous ligand, SDF-1, mediated chemokine signaling in microglia;
Aim II : To determine whether ethanol disrupts gpl20-mediated chemokine signaling in microglia;
Aim III : To determine whether ethanol is able to induce phosphorylation and internalization of the chemokine receptor, CXCR4, mediated by PKC in microglia. This proposal has the potential to elucidate the mechanisms of ethanol neuroprotection in HAD, and provide insight into therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA013361-03
Application #
6650900
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Grandison, Lindsey
Project Start
2002-09-01
Project End
Budget Start
2003-09-01
Budget End
2004-06-04
Support Year
3
Fiscal Year
2003
Total Cost
$20,042
Indirect Cost
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Collins, Michael A; Neafsey, Edward J; Mukamal, Kenneth J et al. (2009) Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 33:206-19