Thrombin signaling and HIV dementia

Summary

Principal Investigator: KATHERINE E CONANT
Abstract: DESCRIPTION (provided by applicant): Pathological evidence suggests that levels of both thrombin and its principal receptor, proteinase activated receptor-1 (PAR-l), are increased in associated with HIV encephalitis. Thrombin can enter the CNS through a damaged blood brain barrier, and it is also produced by immune activated cells of the brain parenchyma. Potential effects of thrombin which may be important to the pathogenesis of HIVD include its ability to degrade matrix proteins that support cell adhesion and survival, as well as its ability to signal through PARs. Activation of endothelial cell PARs has been linked to changes in cell shape, increased chemokine release, and increased adhesion molecule expression. Activation of neuronal PARs has also been demonstrated and is thought to underlie some of the previously reported effects of thrombin on these cells, including neurotoxicity and neurite retraction. Of interest, HIV dementia (HIVD) has been associated with evidence of neurite retraction including dendritic simplification and reduced synaptic density. The responsible mechanisms, however, are not well understood. In the present R21 application, we propose to test the hypothesis that thrombin acts on specific neuronal PARs to stimulate neurite retraction through the activation of glycogen synthase kinase 3b (GSK3b), a critical mediator of cell shape and survival. GSK3b has been shown to phosphorylate microtubule-associated proteins including tau, and increased phosphorylation of tau has been linked to neurite retraction in a number of experimental paradigms. We will also identify the mechanisms that underlie thrombin's effects on GSK3b. While previous studies have suggested that G protein subtypes typically associated with alterations in Rho GTPase activity can affect the activity of GSK3b, none have shown that those linked to decreased adenylate cyclase activity can do the same. We will therefore test the hypothesis that thrombin stimulation of neurons affects both a decrease in PKA-dependent serine phosphorylation and an increase in RhoA dependent tyrosine phosphorylation of GSK3b. The results from these experiments should prompt future studies to determine whether other HIVD related stimuli that cause neurite retraction target similar pathways. Ultimately, we hope to gain a better understanding of mechanisms that contribute to altered neuronal morphology in the setting of HIVD, and to determine whether it may be useful to target GSK3b and/or specific G protein coupled receptors.
Funding Period: 2003-12-01 - 2006-11-30
more information: NIH RePORT