Sanjay B. Maggirwar, M.B.A., Ph.D.

We hypothesize that CD40 signaling in microglia and in brain microvascular endothelial cells (BMVEC) may synergize with the effects of candidate HIV-1 neurotoxins, such as Tat or platelet activating factor (PAF), and play a pivotal role in HAD. We will investigate this in three specific aims. In Aim 1, we will analyze synergistic effects of candidate HIV-1 neurotoxins and CD40 engagement on inflammatory gene expression in human macrophages and microglial cells, by examining signaling mechanisms associated with CD40 engagement, including analyses of the anti-inflammatory effects of NF-kappaB inhibitors, minocycline and glitazones. In Aim 2, we will examine the role of CD40 engagement in monocyte adhesion and migration through an artificial BBB in response to HIV-1 neurotoxins, by determining specific signaling events that lead to increased expression of adhesion and inflammatory molecules in human BMVEC. Additionally, we will determine whether down-modulation of CD40 expression, following CD40-specific RNA interference or exposure to pharamcologic inhibitors (statins), antagonizes cellular migration through BBB. Finally, in Aim 3, we will use CD40 KO mice, CD40L KO mice or wild-type mice treated with a monoclonal antibody specific for mouse CD40L that disrupts CD40-CD40L interaction, to investigate whether the interplay between CD40- and HIV-1 neurotoxin-mediated signaling also contributes to the CNS inflammation and impaired synaptic transmission in vivo. Collectively, these investigations will identify novel therapeutic strategies that may enhance neuronal function and survival in neuroAIDS.
B. Endogenous mechanisms of neuroprotection: This project uses in vitro rodent and human models to investigate how mixed lineage kinases,(MLKs), acting on pro-apoptotic c-Jun NH2 terminal kinase (JNK), are involved in the activation of mononuclear phagocytes and damage to synaptic architecture. Additionally, this project investigates the functional consequences of MLK3 inhibition in ex vivo brain tissue slices and tests the efficacy of new compounds, synthesized by Biofocus, LTD that inhibit MLK3, to deactivate mononuclear phagocytes, preserve synaptic architecture, and restore synaptic transmission during exposure to HIV-1 neurotoxins.
C. Crosstalk between GSK3beta and NF-kappaB signaling pathway: The overlap between NF-kappaB signaling events and GSK3beta regulation suggests that GSK3beta may be involved in NF-kappaB signaling and that disregulation of GSK3beta activity could potentially disrupt the NF-kappaB response, leading to cell death. Based on this notion, we are investigating, (1) whether HIV toxin Tat-mediated activation of GSK3beta is capable of disrupting activation of endogenous NF-kappaB,; and (2) since overexpression of NF-kappB can prevent cell death induced by Tat, whether it also is able to override toxic effects of irregular activation of GSK3beta.

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