AIDS-RELATED NEUROTOXCITY: GP120 AND CHEMOKINES

Burnham Institute For Medical Research, La Jolla CA

Investigators

Linked publications & trials

Abstract

Description (adapted from applicant's abstract): This studies outlined in this application are based on the general hypothesis that "engagement of chemokine receptors by gp120 directly on neurons and astrocytes is insufficient to cause neurodegeneration under pathologically relevant conditions, but may facilitate the deleterious effects of activated microglia/M by modulating, for example, the excitability and calcium levels of neurons." The five specific aims organize five approaches and sets of experiments: 1. To determine if alpha- or beta-chemokines ameliorate gp120-induced neuronal apoptosis in 'mixed' neuronal/glial rodent and human retinal and cerebrocortical cultures. Both R5 and XR gp120s will be used in these cell culture studies. 2. To assess whether gp120-induced injury is predominantly mediated via microglia/M release of neurotoxins, by direct action on neurons or by both mechanisms; these distinctions will be examined by blocking M using threonine-lysine-proline (TKP) tripeptide. 3. To determine whether chemokines directly or indirectly signal neurons via G-protein pathways using fluorescent dyes to study calcium flux, and also to see if chemokine signaling interferes with gp120-induced signaling as well as monitor intracellular signaling via the JNK, ERK and p38 PK pathways. 4. Use of the gp120 transgenic mouse to determine whether chronic intracerebral injection of TKP affords local neuroprotection, thereby implicating M mediation. 5. Use neuronal cultures derived from CXCR4- and CCR5 knockout mice to assess the necessity of these receptors on in vitro gp120-induced toxicity.