Project 1 will use in vitro and in vivo models to investigate signal transduction pathways that transduce activation of mixed lineage kinase type 3 (MLKS), because we hypothesize that pathologic activation of MLKS leads to neuroinflammation and loss of synaptic plasticity in HAND. Using 2nd generation small molecule MLK3 inhibitors (designated as our lead compound URMC-099 or their descendant congeners, URMC-099c*) developed by our industry partner, Califia Bio Inc in Project 2, we have demonstrated that URMC-099 blocks pro-inflammatory cytokine production from HIV-1 Tat-stimulated monocyte-derived macrophage and microglia in vitro, as well as prevents leukocyte trafficking in CNS vasculature and damage to synaptic architecture following stereotactic injection of Tat in the CNS in vivo. Additionally, we have demonstrated that MLKS inhibition with these inhibitors increases the neuronal Tri

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program Projects (P01)
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Special Emphasis Panel (ZMH1-ERB-M)
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University of Rochester
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