MPBC Faculty - Ernest Moore

Ion Channel Biology and Toxicology of Auditory Cells. Our laboratory is investigating potassium (K+) channels (KCNQ or Kv7.x super family) of hair cells. Metals such as lead (Pb), mercury (Hg) or copper (Cu) are applied to the cells in concentrations that are below, similar to, or exceed recommended health standards. We as well as others have demonstrated that various KCNQ channels of auditory cells play an important role in the processing of auditory information. Pb, Hg, and Cu down regulate the ionic currents and signal transduction pathways of these cells resulting in hearing loss and deafness. Human genetics and genomics have revealed also that mutations in hundreds of genes can cause profound and progressive hearing impairment in young adults and children. Two-thirds of these individuals have non-syndromic hearing impairment, where altered auditory function is the only obvious clinical result of gene mutation. Some of the mutated genes appear to define a pathway for potassium ion recycling, which transports K+ from the hair cell through supporting cells connected by gap junctions back into the endolymph that baths the organ of Corti of the cochlea. Mutations in three different K+ channel genes result in progressive hearing loss and combined with mutations in gap-junctional proteins are responsible for more than 25% of hereditary hearing impairment in Americans. Mutations in KCNQ4, which is highly expressed in outer hair cells, inner hair cells and spiral ganglion cells of the inner ear, cause progressive hearing loss.

There is insufficient knowledge about the regulation of KCNQ4 in the auditory system, although Ca2+/calmodulin, phosphatidylinositides, or phosphorylation mechanisms may regulate this and other members of the KCNQ family. We were the first to demonstrate the involvement of KCNQ2 and KCNQ3 in the generation of the M-current in the mammalian OHC. We utilize a multidisciplinary systems biology approach (Patch Clamp Electrophysiology, Fluorescence Microscopy, Molecular Biology, Proteomics, Virtual Cell Modeling) to investigate the regulation of KCNQ4 channels, and how dysfunction/knock down (e.g., morpholino or RNAi technology) of genes impacts both K+ channel and cellular signaling leading to degeneration of hair cells and thus progressive hearing loss. Previous and ongoing investigations in our laboratory may provide a better understanding of the underlying basic mechanisms for abnormal disease states or channelopathies of hair cells. Our research may lead to drug discovery targets that might be used to prevent or treat hearing loss and deafness in children.

Ion Channels Bian, J-T., Yeh, J.Z., Aistrup, G.L., Narahashi, T., Moore, E.J. (2002) Inhibition of K+ currents of outer hair cells in guinea pig cochlea by fluoxetine. Eur. J. Pharmacol., 453, 159-166. Liang G, Järlebark L, Ulfendahl M, Moore E.J. (2003) Mercury (Hg²⁺) suppression of potassium currents of outer hair cells. Neurotox & Teratology 25, 349-359. Liang G, Järlebark L, Ulfendahl M, Bian J-T, Moore E.J. (2004) Lead (Pb2+) modulation of potassium currents of guinea pig outer hair cells. Neurotox & Teratology 26, 253-256. Liang G, Moore E.J., Ulfendahl M, Rydqvist B, Järlebark L (2005) An M-like potassium current in the guinea pig cochlea. Acta Oto Rhino Laryngol, .ORL 67, 75-82 PubMed Reference Lookup	Ernest Moore
	Research Professor Office: Morton Bldg. 7-615 (312) 503-1736 Lab: Morton Bldg. 7-614 (312) 503-2658 mooreer@northwestern.edu Ion Channel Biology and Toxicology of Auditory Cells. Our laboratory is investigating potassium (K+) channels (KCNQ or Kv7.x super family) of hair cells. Metals such as lead (Pb), mercury (Hg) or copper (Cu) are applied to the cells in concentrations that are below, similar to, or exceed recommended health standards. We as well as others have demonstrated that various KCNQ channels of auditory cells play an important role in the processing of auditory information. Pb, Hg, and Cu down regulate the ionic currents and signal transduction pathways of these cells resulting in hearing loss and deafness. Human genetics and genomics have revealed also that mutations in hundreds of genes can cause profound and progressive hearing impairment in young adults and children. Two-thirds of these individuals have non-syndromic hearing impairment, where altered auditory function is the only obvious clinical result of gene mutation. Some of the mutated genes appear to define a pathway for potassium ion recycling, which transports K+ from the hair cell through supporting cells connected by gap junctions back into the endolymph that baths the organ of Corti of the cochlea. Mutations in three different K+ channel genes result in progressive hearing loss and combined with mutations in gap-junctional proteins are responsible for more than 25% of hereditary hearing impairment in Americans. Mutations in KCNQ4, which is highly expressed in outer hair cells, inner hair cells and spiral ganglion cells of the inner ear, cause progressive hearing loss. There is insufficient knowledge about the regulation of KCNQ4 in the auditory system, although Ca2+/calmodulin, phosphatidylinositides, or phosphorylation mechanisms may regulate this and other members of the KCNQ family. We were the first to demonstrate the involvement of KCNQ2 and KCNQ3 in the generation of the M-current in the mammalian OHC. We utilize a multidisciplinary systems biology approach (Patch Clamp Electrophysiology, Fluorescence Microscopy, Molecular Biology, Proteomics, Virtual Cell Modeling) to investigate the regulation of KCNQ4 channels, and how dysfunction/knock down (e.g., morpholino or RNAi technology) of genes impacts both K+ channel and cellular signaling leading to degeneration of hair cells and thus progressive hearing loss. Previous and ongoing investigations in our laboratory may provide a better understanding of the underlying basic mechanisms for abnormal disease states or channelopathies of hair cells. Our research may lead to drug discovery targets that might be used to prevent or treat hearing loss and deafness in children. Return to Faculty MPBC Home

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