Our long term goal is to develop effective agents for AIDS dementia complex. The purpose of this project is to investigate if green tea EGCG, a known inhibitor of signal transducer and activation of transcription 1 (STAT1), could attenuate AIDS-like neuronal damage through disruption STAT1 signaling in mice exposed to IFN-g with HIV-1 proteins gp120 and Tat. A state of immune activation characterized by increased levels of pro-inflammatory cytokines is widely regarded as an important factor leading to AIDS dementia-like neuronal damage and a key regulator for pro-inflammatory signaling in neurons is STAT1. STAT1 activation is involved in neuronal injury/death associated with brain ischemia, as well as AIDS dementia. Moreover its """"""""activator"""""""" IFN-g, has been shown to be elevated both in the cerebrospinal fluid and brains of HIV positive individuals. Results from our pilot studies suggest that IFN-g enhances the neurotoxic effects of gp120 and Tat. Further, AIDS dementia-like neuronal damage from this combined insult was largely attenuated in STAT1 deficient neurons. We and others have shown that the treatment of primary neurons with EGCG reduces STAT1 activation and resultant neuronal injury in models of AIDS dementia and stroke, respectively. We hypothesize that EGCG treatment will decrease AIDS dementia-like neuronal damage via STAT1 suppression.
Aim 1 is to establish a mouse model representative of the possible neuronal damage exhibited in AIDS dementia.
Aim 2 will characterize the role of STAT1 in mediating neuronal injury induced by IFN-g and gp120 and Tat in mice. To this end we will compare the neuronal damage in STAT1 deficient mice to control mice after intracerebroventricular injection of IFN-g with gp120 or Tat. We expect STAT1 deficient mice will show a marked decrease in AIDS dementia-like neuronal damage compared to control.
Aim 3 will investigate the effects of EGCG on inhibition of the neuronal damage resulting from IFN-g mediated STAT1 activation in the presence of gp120 or Tat in mice. Here we also plan to delineate the most effective EGCG intraperitoneal injection by comparing AIDS dementia-like neuronal damage in prophylactic, therapeutic, and combined prophylactic/therapeutic paradigms. We hypothesize that EGCG-treated mice will show significant decreases in AIDS dementia-like neuronal damage when compared to vehicle-treated mice. These data should lay the foundation for further research leading to human trials in the near future. Narrative: The purpose of this project is to investigate if green tea derived EGCG could attenuate AIDS-like neuronal damage in the mouse model. We hypothesize that EGCG-treated mice will show significant decreases in AIDS dementia-like neuronal damage when compared to vehicle-treated mice. These data should lay the foundation for further research leading to human trials in the near future. ? ? ?
