The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Philine Wangemann - One of the best experts on this subject based on the ideXlab platform.
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Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression.
PloS one, 2010Co-Authors: Hyoung-mi Kim, Philine WangemannAbstract:Mutations of SLC26A4 are among the most prevalent causes of hereditary deafness. Deafness in the corresponding mouse model, Slc26a4−/−, results from an abnormally enlarged cochlear lumen. The goal of this study was to determine whether the cochlear enlargement originates with defective cochlear fluid transport or with a malfunction of fluid transport in the connected compartments, which are the Vestibular Labyrinth and the endolymphatic sac. Embryonic inner ears from Slc26a4+/− and Slc26a4−/− mice were examined by confocal microscopy ex vivo or after 2 days of organ culture. Culture allowed observations of intact, ligated or partially resected inner ears. Cochlear lumen formation was found to begin at the base of the cochlea between embryonic day (E) 13.5 and 14.5. Enlargement was immediately evident in Slc26a4−/− compared to Slc26a4+/− mice. In Slc26a4+/− and Slc26a4−/− mice, separation of the cochlea from the Vestibular Labyrinth by ligation at E14.5 resulted in a reduced cochlear lumen. Resection of the endolymphatic sacs at E14.5 led to an enlarged cochlear lumen in Slc26a4+/− mice but caused no further enlargement of the already enlarged cochlear lumen in Slc26a4−/− mice. Ligation or resection performed later, at E17.5, did not alter the cochlea lumen. In conclusion, the data suggest that cochlear lumen formation is initiated by fluid secretion in the Vestibular Labyrinth and temporarily controlled by fluid absorption in the endolymphatic sac. Failure of fluid absorption in the endolymphatic sac due to lack of Slc26a4 expression appears to initiate cochlear enlargement in mice, and possibly humans, lacking functional Slc26a4 expression.
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Cochlear and Vestibular Function and Dysfunction
Physiology and Pathology of Chloride Transporters and Channels in the Nervous System, 2010Co-Authors: Daniel C. Marcus, Philine WangemannAbstract:This chapter focuses on cellular ion transport mechanisms in the inner ear, their dependence on Clˉ and their physiological role in generating the major electrochemical gradients on which sensory transduction depends. It also outlines the cochlea and the Vestibular Labyrinth of the inner ear. The inner ear consists of the coiled cochlea and the Vestibular Labyrinth. Three semicircular canals that originate from the utricle, the saccule and the endolymphatic duct and sac make up the Vestibular Labyrinth. The luminal fluid in the inner ear is called endolymph. The inner ear transduces the mechanical stimuli into electrical signals that are ultimately encoded into neuronal action potentials. The encoded information is transmitted by afferent neurons to central processing regions in the brain. The sensory process is guarded by intricate feedback mechanisms that include systems of efferent innervation that terminate on the afferent nerves and on the sensory cells in the inner ear. The mechano-sensory transduction in the cochlea and in the Vestibular Labyrinth depends on large electrochemical gradients and an unusual fluid composition in the luminal compartment of the inner ear.
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k cycling and its regulation in the cochlea and the Vestibular Labyrinth
Audiology and Neuro-otology, 2002Co-Authors: Philine WangemannAbstract:Potassium (K + ) plays a very important role in the cochlea. K + is the major cation in endolymph and the charge carrier for sensory transduction and the generation of the endocochlear potential. The importance of K + handling in the cochlea is marked by the discovery of several forms of hereditary deafness that are due to mutations of K + channels. Deafness results from mutations of KCNQ4, a K + channel in the sensory hair cells, as well as from mutations of the gap junction proteins GJB2, GJB3 and GJB6 that may facilitate cell-to-cell movements of K + . Deafness results also from mutations of KCNQ1 or KCNE1, subunits of a K + channel that carries K + from strial marginal cells and Vestibular dark cells into endolymph. Further, deafness results from mutations of KCNJ10, a K + channel that generates the endocochlear potential in conjunction with the high K + concentration in strial intermediate cells and the low K + concentration in the intrastrial fluid spaces. This review details recent advances in the understanding of K + transport and its regulation in the cochlea and the Vestibular Labyrinth.
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K(+) cycling and its regulation in the cochlea and the Vestibular Labyrinth.
Audiology & neuro-otology, 2002Co-Authors: Philine WangemannAbstract:Potassium (K + ) plays a very important role in the cochlea. K + is the major cation in endolymph and the charge carrier for sensory transduction and the generation of the endocochlear potential. The importance of K + handling in the cochlea is marked by the discovery of several forms of hereditary deafness that are due to mutations of K + channels. Deafness results from mutations of KCNQ4, a K + channel in the sensory hair cells, as well as from mutations of the gap junction proteins GJB2, GJB3 and GJB6 that may facilitate cell-to-cell movements of K + . Deafness results also from mutations of KCNQ1 or KCNE1, subunits of a K + channel that carries K + from strial marginal cells and Vestibular dark cells into endolymph. Further, deafness results from mutations of KCNJ10, a K + channel that generates the endocochlear potential in conjunction with the high K + concentration in strial intermediate cells and the low K + concentration in the intrastrial fluid spaces. This review details recent advances in the understanding of K + transport and its regulation in the cochlea and the Vestibular Labyrinth.
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K+ cycling and the endocochlear potential.
Hearing research, 2002Co-Authors: Philine WangemannAbstract:Sensory transduction in the cochlea and the Vestibular Labyrinth depends on the cycling of K+. In the cochlea, endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells into perilymph via basolateral K+ channels including KCNQ4. K+ may be taken up by fibrocytes in the spiral ligament and transported from cell to cell via gap junctions into strial intermediate cells. Gap junctions may include GJB2, GJB3 and GJB6. K+ is released from the intermediate cells into the intrastrial space via the KCNJ10 K+ channel that generates the endocochlear potential. From the intrastrial space, K+ is taken up across the basolateral membrane of strial marginal cells via the Na+/2Cl-/K+ cotransporter SLC12A2 and the Na+/K+-ATPase ATP1A1/ATP1B2. Strial marginal cells secrete K+ across the apical membrane into endolymph via the K+ channel KCNQ1/KCNE1, which concludes the cochlear cycle. A similar K+ cycle exists in the Vestibular Labyrinth. Endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells via basolateral K+ channels including KCNQ4. Fibrocytes connected by gap junctions including GJB2 may be involved in delivering K+ to Vestibular dark cells. Extracellular K+ is taken up into Vestibular dark cells via SLC12A2 and ATP1A1/ATP1B2 and released into endolymph via KCNQ1/KCNE1, which concludes the Vestibular cycle. The importance of K+ cycling is underscored by the fact that mutations of KCNQ1, KCNE1, KCNQ4, GJB2, GJB3 and GJB6 lead to deafness in humans and that null mutations of KCNQ1, KCNE1, KCNJ10 and SLC12A2 lead to deafness in mouse models.
Tracy Miesner - One of the best experts on this subject based on the ideXlab platform.
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SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
2016Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Raoul Nelson, Nicolas Picard, Dominique Eladari, Tracy Miesner, Andrew J. GriffithAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4D/D mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4D/D line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy wil
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SLC26A4 targeted to the endolymphatic sac rescues hearing and balance in Slc26a4 mutant mice.
PLoS genetics, 2013Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Nicolas Picard, Dominique Eladari, Raoul D. Nelson, Régine Chambrey, Tracy MiesnerAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.
Joel D. Sanneman - One of the best experts on this subject based on the ideXlab platform.
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SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
2016Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Raoul Nelson, Nicolas Picard, Dominique Eladari, Tracy Miesner, Andrew J. GriffithAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4D/D mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4D/D line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy wil
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SLC26A4 targeted to the endolymphatic sac rescues hearing and balance in Slc26a4 mutant mice.
PLoS genetics, 2013Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Nicolas Picard, Dominique Eladari, Raoul D. Nelson, Régine Chambrey, Tracy MiesnerAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.
Kiyotaka Murata - One of the best experts on this subject based on the ideXlab platform.
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R447 – Temporal Bone Histopathology in Acute Lymphocytic Leukemia
Otolaryngology-Head and Neck Surgery, 2008Co-Authors: Kyoichi Terao, Michael M. Paparella, Sebahattin Cureoglu, Schachern Patricia, Norimasa Morita, Nomiya Rie, Kiyotaka MurataAbstract:ProblemThere are reports of hearing loss, tinnitus, and/or vertigo in patients with leukemia. However, there is no human temporal bone study of a large number of cases specific to acute lymphocytic leukemia. We studied the correlation between clinical otologic complaints and temporal bone histopathology in patients with this disease.MethodsClinical otologic complaints and histologic findings were evaluated in 13 patients (25 temporal bones) with acute lymphocytic leukemia.ResultsNine patients had a history of clinical otologic complaints including: hearing loss in 5 patients; otalgia in 3; otorrhea in 3; and dizziness in 2. Hemorrhage was seen most commonly in the middle ear in 10 patients, but was also evident in the cochlea in 5 and the Vestibular Labyrinth in 2. Leukemic infiltration was observed in the petrous apex in 12 patients, in the middle ear in 6, the cochlea in 5, the Vestibular Labyrinth in 2 and the internal auditory canal in 3. Inflammatory cell infiltration was also seen in the cochlear la...
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R447 – Temporal Bone Histopathology in Acute Lymphocytic Leukemia
Otolaryngology–Head and Neck Surgery, 2008Co-Authors: Kyoichi Terao, Michael M. Paparella, Sebahattin Cureoglu, Schachern Patricia, Norimasa Morita, Nomiya Rie, Kiyotaka MurataAbstract:Problem There are reports of hearing loss, tinnitus, and/or vertigo in patients with leukemia. However, there is no human temporal bone study of a large number of cases specific to acute lymphocytic leukemia. We studied the correlation between clinical otologic complaints and temporal bone histopathology in patients with this disease. Methods Clinical otologic complaints and histologic findings were evaluated in 13 patients (25 temporal bones) with acute lymphocytic leukemia. Results Nine patients had a history of clinical otologic complaints including: hearing loss in 5 patients; otalgia in 3; otorrhea in 3; and dizziness in 2. Hemorrhage was seen most commonly in the middle ear in 10 patients, but was also evident in the cochlea in 5 and the Vestibular Labyrinth in 2. Leukemic infiltration was observed in the petrous apex in 12 patients, in the middle ear in 6, the cochlea in 5, the Vestibular Labyrinth in 2 and the internal auditory canal in 3. Inflammatory cell infiltration was also seen in the cochlear Labyrinth in 4 patient, the Vestibular Labyrinth in 5 and the modiolus in 1. Otitis media with hyperplasia of subepithelial fibrous tissue was seen in 10 patients. Three patients had granulation tissue extending into the middle ear or mastoid. Conclusion Ear involvement is a common finding in patients with acute lymphocytic leukemia. Significance With prolonged survival due to new chemotherapeutics, the diagnosis and treatment of non-hematopoietic system complications such as ear problems due to acute lymphocytic leukemia have become more important. Support International Hearing Foundation, Hubbard Foundation, Starkey Foundation.
Nicolas Picard - One of the best experts on this subject based on the ideXlab platform.
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SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice
2016Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Raoul Nelson, Nicolas Picard, Dominique Eladari, Tracy Miesner, Andrew J. GriffithAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4D/D mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4D/D line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy wil
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SLC26A4 targeted to the endolymphatic sac rescues hearing and balance in Slc26a4 mutant mice.
PLoS genetics, 2013Co-Authors: Joel D. Sanneman, Donald G. Harbidge, Fei Zhou, Taku Ito, Nicolas Picard, Dominique Eladari, Raoul D. Nelson, Régine Chambrey, Tracy MiesnerAbstract:Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the Vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the Vestibular Labyrinth and the endolymphatic sac. Slc26a4Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous Labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the Vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous Labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the Vestibular Labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4.