The TRPM4 ion channel is a member of the Transient Receptor Potential Melastatin family, and is permeable to monovalent cations but impermeable to calcium. Deletion of this gene in mice ameliorates the course of disease progression in an animal model of multiple sclerosis (MS). TRPM4 deletion does not influence the disease-relevant immune response in knockout mice in the animal model of MS.
TRPM4 is expressed in murine and human neurons, and is upregulated in axons in experimental autoimmune encephalomyelitis (EAE) and MS lesions. TRPM4 deletion substantially protects neuronal cells from excitotoxic challenges and energy deficiency; in part, this is thought to be due to excessive sodium influx through activated TRPM4 channels in diseased axons. TRPM4 blockade by glibenclamide, an unspecific blocker of this channel, exerts a similar neuroprotective property as its genetic deletion.
To find a specific inhibitor of TRPM4 channels to further define their role in MS, we screened a library of 250K small drug-like molecules using cells expressing human TRPM4 channels with a membrane potential dye readout. Hits were confirmed and profiled for concentration-dependent activity at TRPM4, selectivity against TRPM5 and host HEK cells, and tested in Automated Patch Clamp assays. Selected antagonist molecules from multiple chemical series are being optimized for testing in vivo.
Manuel Friese, MD, Professor of Neuroimmunology and Director of the Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf
Manuel Friese studied medicine at the Universities of Hamburg, Oxford and University College London and received his MD in 2001. He completed his neurology training at the Universities of Tübingen and Hamburg. After his postdoctoral training at the University of Oxford from 2004–2008, he started his laboratory as an Emmy Noether research fellow of the German Research Foundation (DFG) at the University of Hamburg. Since 2013 he has been consultant neurologist and Professor of Neuroimmunology at the University of Hamburg and since 2014, director of the Institute of Neuroimmunology and Multiple Sclerosis (INIMS). His laboratory focuses on inflammatory and neurodegenerative aspects of neuroimmunological and neuroinfectious diseases.
Stephen Hess, PhD, Research Leader, Ion Channels, Evotec AG
Stephen obtained a BS in Zoology, MS in Biology and a PhD in Biology and did Postdoctoral studies in two labs in the US. His career started with SIBIA Neurosciences in La Jolla, CA, where he helped build cell lines and assays for HTS, Hit-to-lead, and Lead Optimization activities on Ionotropic and Metabotropic Glutamate receptors. SIBIA was acquired by Merck & Co, and he continued the focus on Ion Channel Drug Discovery as a Biology Project Leader on multiple projects there. He next joined Invitrogen in Madison, WI, and led an Ion Channel team focused on custom assay development. Next,he moved to Millipore in St. Louis, MO, and managed an R&D team that built GPCR & Ion Channel cell lines used in profiling services offered by the Drug Discovery unit there. He joined Evotec in Hamburg, Germany in 2012 and leads the Ion Channel Department there, which is focused on Integrated Drug Discovery collaborations for Ion Channel & CNS targets.
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Application areas: Cell Biology, High Content Screening, Phenotypic Screening, Target Identification, Target Validation
Therapeutic areas: Cancer, Oncology, Metabolic, Inflammation, CNS, Cardiovascular, Rare Diseases
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