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
Zhang, Gang; Guo, Dongwei; Dash, Prasanta K et al. (2016) The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12:109-22
Dong, Weiguo; Embury, Christine M; Lu, Yaman et al. (2016) The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation 13:184
Guo, Dongwei; Zhou, Tian; Araínga, Mariluz et al. (2016) Creation of a Long-Acting Nanoformulated 2',3'-Dideoxy-3'-Thiacytidine. J Acquir Immune Defic Syndr :
Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y et al. (2016) HIV-1 cellular and tissue replication patterns in infected humanized mice. Sci Rep 6:23513
Olson, Katherine E; Gendelman, Howard E (2016) Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease. Curr Opin Pharmacol 26:87-95
Olson, Katherine E; Bade, Aditya N; Schutt, Charles R et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease. Neurotherapeutics 13:635-46
Li, Weizhe; Tong, Hsin-I; Gorantla, Santhi et al. (2016) Neuropharmacologic Approaches to Restore the Brain's Microenvironment. J Neuroimmune Pharmacol 11:484-94
Singh, Dhirender; McMillan, JoEllyn; Hilaire, James et al. (2016) Development and characterization of a long-acting nanoformulated abacavir prodrug. Nanomedicine (Lond) 11:1913-27
Sajja, Balasrinivasa R; Bade, Aditya N; Zhou, Biyun et al. (2016) Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγc(null) Mouse Brain Atlas. J Neuroimmune Pharmacol 11:133-41
Bade, Aditya N; Gorantla, Santhi; Dash, Prasanta K et al. (2016) Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. Mol Neurobiol 53:3286-97

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