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Treatments to stop gray matter degeneration are needed to prevent progressive disability in multiple sclerosis (MS). We tested whether inhibiting mixed-lineage kinases (MLKs), which can drive inflammatory microglial activation and neuronal degeneration, could protect hippocampal synapses in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates the excitatory synaptic injury that occurs widely within the gray matter in MS. URMC-099, a broad spectrum MLK inhibitor with additional activity against leucine-rich repeat kinase 2 (LRRK2) and other kinases, prevented loss of PSD95-positive postsynaptic structures, shifted activated microglia toward a less inflammatory phenotype, and reversed deficits in hippocampal-dependent contextual fear conditioning in EAE mice when administered after the onset of motor symptoms. A narrow spectrum inhibitor designed to be highly selective for MLK3 failed to protect synapses in EAE hippocampi, and could not rescue cultured neurons from trophic deprivation in an in vitro model of MLK-driven neuronal degeneration. These results suggest that URMC-099 may have potential as a neuroprotective treatment in MS and demonstrate that a broad spectrum of inhibition against a combination of MLK and other kinases is more effective in neuroinflammatory disease than selectively targeting a single kinase.
Pubmed ID: 30627663 RIS Download
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3D image analysis software to visualize, analyze and validate 3D fluorescence images from a wide range of confocal microscopy, widefield and high content screening systems. It is fully integrated for a seamless user experience.
View all literature mentionsA national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.
View all literature mentionsAn independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.
View all literature mentionsA commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
View all literature mentionsSoftware application with data analysis tools and spreadsheet templates to track and visualize data. It is used to manage and process data.
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis polyclonal targets Mouse Fc gamma RI/CD64 Affinity Purified Ab
View all literature mentionsThis monoclonal targets TMEM119
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View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis monoclonal targets Mouse Neutrophil
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis monoclonal targets α-tubulin
View all literature mentionsThis monoclonal targets CD86 (B7-2)
View all literature mentionsThis monoclonal targets MAP2
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis monoclonal targets Phospho-c-Jun (Ser73)
View all literature mentionsThis monoclonal targets TNF-α
View all literature mentionsThis monoclonal targets Mouse IL-10
View all literature mentionsThis monoclonal targets TMEM119
View all literature mentionsThis monoclonal targets TNF-α
View all literature mentionsThis monoclonal targets CD68
View all literature mentionsThis monoclonal targets MAP2
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis polyclonal targets Mouse Fc gamma RI/CD64 Affinity Purified Ab
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis unknown targets Mouse INOS
View all literature mentionsThis monoclonal targets CD86 (B7-2)
View all literature mentionsThis monoclonal targets Mouse IL-10
View all literature mentionsThis monoclonal targets Mouse Neutrophil
View all literature mentionsThis monoclonal targets Phospho-c-Jun (Ser73)
View all literature mentionsThis monoclonal targets α-tubulin
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis unknown targets Mouse INOS
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