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

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH064570-13
Application #
8664423
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$438,171
Indirect Cost
$154,241
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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