We have established transgenic (tg) models in which cerebral expression of HIV-1 proteins induces glial and neuronal alterations that resemble neuropathologic changes found in humans with HIV-1 associated dementia (1). Here we propose to use these tg models to further characterize the processes that underlie HIV-induced neurotoxicity in vivo and to identify critical targets for therapeutic interventions.
Aim #1 : Compare GFAP-gp120 tg mice with non-tg controls with respect to: a) neuronal susceptibility to exogenously administered excitotoxic amino acids, b) evidence for alterations in cerebral calcium homeostasis, and c) evidence for neuronal apoptosis.
Aim #2 : Treat GFAP-gp120 tg mice with drugs aimed at specific neuropathogenic pathways (including meman-tine, other adamantanes, nimodipine, nitroglycerin, and phenylbutylnitrone) and compare the extent of their nervous system damage with that of sham-treated controls.
Aim #3 : Generate bigenic mice in which brain expression of gp120 is combined with the expression of superoxide dismutase (SOD) or mutated glutamate receptor subunits. Analyze the nervous system of bigenic mice at the structural and molecular level and compare the results with those obtained in the singly tg parental strains.
Aim #4 : Determine whether the expression of gp120 in the brains of tg mice is associated with functional neuronal/behavioral alterations. If so, assess the responsiveness of these abnormalities to the manipulations outlined in Aims #2 and #3 above. The proposed experiments are expected to help determine the molecular processes underlying gp120 neurotoxicity in vivo. They will also allow the preclinical assessment of therapeutic strategies that could benefit patients with HIV- 1 associated dementia and related disorders.
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|Yeh, M W; Kaul, M; Zheng, J et al. (2000) Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of l -cysteine. J Immunol 164:4265-70|