CYTOSOLIC REGULATION OF INNER EAR ION TRANSPORT

Summary

Principal Investigator: Lorraine A Everett
Abstract: Cytosolic Regulation of Inner Ear Ion Transport Defects in potassium cycling, gap junction-mediated intercellular communication and cochlear metabolism are re- sponsible for the ovelwhelming majority of hearing impairments This proposal is designed to further our under- standing of potassium cycling, by determining the role of connexins in potassium cycling, glutamate metabolism and the prevention of apoptosis and to determine whether a monocarboxylate shuttle contributes to meet the enel- getic needs of the cochlea In detail, under Specific Aim 1, we will define the path of potassium cycling that leads from the hair cells in the organ of Corti to strial marginal cells in stria vascularis Under Specific Aim 2, we will detelmine the subunit composition of the potassium channels KCNQ1 in strial marginal cells, KCNQ4 in outer hair cells and KCNJ10 in strial intermediate cells These potassium channels are associated with hereditary forms of deafness KCNQ1 mediates potassium secletion into endolyinph, KCNQ4 mediates potassium lelease out of outer hair cells and KCNJ10 generates the endocochlear potential Each of these potassium channels is thus a major con- tributor to potassium cycling Under Specific Aim 3, we will determine the role of connexins in glutamate metabo- lism and the plevention of apoptosis We hypothesize that glutamate metabolism in the organ of Corti is obligato- rily dependent on connexin-mediated intraceUular communication and that connexin hemichannels in supporting cells limit glutamate release from the inner hair cells We will determine whether the capacity to metabolize glu- tamate is reduced by disruption of connexin-mediated intercellular communication and whether glutamate- induced metabolic stress causes opening of the mitochondrial permeability transition pore to initiate apoptosis Finally, under Specific Aim 4, we propose to test the hypothesis that a monocarboxylate shuttle based in stlia vas- cularis contributes to meet the metabolic needs ot the organ of Colti The completion of these studies will further our understanding of cochlear metabolism and homeostasis and provide a basic undelstanding of the molecular mechanisms that initiate the irreversible loss of sensory function in the inner ear PERFORMANCESiTE(S) (organization,city,state) Kansas State University Cell Physiology Laboratory and Biophysics Laboratory Dept Anatomy & Physiology Manhattan, KS 66506-5802 KEYPERSONNEL See instructionsUsecontinuationpagesasneededto providetherequiredinformationintheformatshownbelow StartwithPrincipalInvestigatorListallotherkeypersonneilnalphabeticaolrder,lastnamefirst Name Organization RoleonProject Wangemann, A Philine Kansas State Univel sity Principal Investigator Albrecht, Beatrice Kansas State University Postdoctoral Fellow Fauser, Claudius Kansas State University Postdoctoral Fellow Maleki, Lili Kansas State University Technician Mmcus, Daniel C Kansas State University Co-Investigator Petit, Christine Pasteur Institute, Paris Consultant Postdoctoral Fellow Scherer, Elias Q Kansas State University Consultant Thalmann, Isolde Washington University Technician White, Erin Kansas State University Wu, Tao Kansas State University Postdoctoral Fellow Zolkiewska, Anna Kansas State University Consultant DisclosurePermissionStatement Applicableto SBIR/STI'ROnly. Seeinstructions[] Yes [] No PHS 398(Rev 05/01) - iSage 2 FormPage2 Wangemann, A. Philine Principal Investigator/Program Director (Last, first, middle) The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,
Funding Period: 1992-01-01 - 2009-12-31
more information: NIH RePORT

Top Publications

  1. pmc Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression
    Hyoung Mi Kim
    Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas, United States of America
    PLoS ONE 5:e14041. 2010
  2. pmc Expression of epithelial calcium transport system in rat cochlea and vestibular labyrinth
    Daisuke Yamauchi
    Cellular Biophysics Laboratory, Dept, Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA
    BMC Physiol 10:1. 2010
  3. pmc A claudin-9-based ion permeability barrier is essential for hearing
    Yoko Nakano
    Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USA
    PLoS Genet 5:e1000610. 2009
  4. pmc Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression
    Philine Wangemann
    Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA
    Am J Physiol Renal Physiol 297:F1435-47. 2009
  5. pmc Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome
    Tao Yang
    Department of Otorhinolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China
    Am J Hum Genet 84:651-7. 2009
  6. ncbi Free radical stress-mediated loss of Kcnj10 protein expression in stria vascularis contributes to deafness in Pendred syndrome mouse model
    Ruchira Singh
    Department of Anatomy and Physiology, Kansas State University, 205 Coles Hall, Manhattan, KS 66506, USA
    Am J Physiol Renal Physiol 294:F139-48. 2008
  7. ncbi Functional significance of channels and transporters expressed in the inner ear and kidney
    Florian Lang
    Department of Physiology, Eberhard Karls University of Tubingen, Gmelinstrasse 5, Tubingen, Germany
    Am J Physiol Cell Physiol 293:C1187-208. 2007
  8. pmc Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model
    Philine Wangemann
    Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas 66506, USA
    Am J Physiol Renal Physiol 292:F1345-53. 2007
  9. pmc Lack of pendrin HCO3- transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels
    Kazuhiro Nakaya
    Cellular Biophysics Laboratory, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506 5802, USA
    Am J Physiol Renal Physiol 292:F1314-21. 2007
  10. pmc Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model
    Sairam V Jabba
    Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA
    BMC Med 4:37. 2006

Scientific Experts

  • Lorraine A Everett
  • Florian Lang
  • Philine Wangemann
  • Sairam V Jabba
  • Ruchira Singh
  • Hyoung Mi Kim
  • Daniel C Marcus
  • Kazuhiro Nakaya
  • Daisuke Yamauchi
  • Richard J H Smith
  • Yoko Nakano
  • Tao Yang
  • Donald G Harbidge
  • Nithya N Raveendran
  • Peter M Snyder
  • Botond Banfi
  • Jose G Gurrola
  • Randy A Nessler
  • Sung H Kim
  • Sui M Chiu
  • Yuzhou Zhang
  • Joel D Sanneman
  • Hao Wu
  • Eric D Green
  • Bruce D Schultz
  • Susan M Wall
  • Nurith Kurn
  • Joe Don Heath
  • Martin Wang
  • Rajanikanth J Maganti
  • Glenn Deng

Detail Information

Publications12

  1. pmc Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression
    Hyoung Mi Kim
    Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas, United States of America
    PLoS ONE 5:e14041. 2010
    ..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...
  2. pmc Expression of epithelial calcium transport system in rat cochlea and vestibular labyrinth
    Daisuke Yamauchi
    Cellular Biophysics Laboratory, Dept, Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA
    BMC Physiol 10:1. 2010
    ..We recently reported the expression of mRNA for a Ca2+-absorptive transport system in primary cultures of semicircular canal duct (SCCD) epithelium...
  3. pmc A claudin-9-based ion permeability barrier is essential for hearing
    Yoko Nakano
    Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa, USA
    PLoS Genet 5:e1000610. 2009
    ..Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function...
  4. pmc Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression
    Philine Wangemann
    Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA
    Am J Physiol Renal Physiol 297:F1435-47. 2009
    ....
  5. pmc Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome
    Tao Yang
    Department of Otorhinolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, PR China
    Am J Hum Genet 84:651-7. 2009
    ..Our results link KCNJ10 mutations with EVA/PS and provide further support for the model of EVA/PS as a multigenic complex disease...
  6. ncbi Free radical stress-mediated loss of Kcnj10 protein expression in stria vascularis contributes to deafness in Pendred syndrome mouse model
    Ruchira Singh
    Department of Anatomy and Physiology, Kansas State University, 205 Coles Hall, Manhattan, KS 66506, USA
    Am J Physiol Renal Physiol 294:F139-48. 2008
    ..These data demonstrate that free radical stress provides a link between loss of pendrin and loss of Kcnj10 in Slc26a4(-/-) mice and possibly in human patients suffering from Pendred syndrome...
  7. ncbi Functional significance of channels and transporters expressed in the inner ear and kidney
    Florian Lang
    Department of Physiology, Eberhard Karls University of Tubingen, Gmelinstrasse 5, Tubingen, Germany
    Am J Physiol Cell Physiol 293:C1187-208. 2007
    ..Thus, defects of channels and transporters expressed in the kidney and inner ear result in simultaneous dysfunctions of these seemingly unrelated organs...
  8. pmc Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model
    Philine Wangemann
    Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas 66506, USA
    Am J Physiol Renal Physiol 292:F1345-53. 2007
    ..Degeneration of the hair cells closes a window of opportunity to restore the normal development of hearing in Slc26a4(-/-) mice and possibly human patients suffering from Pendred syndrome...
  9. pmc Lack of pendrin HCO3- transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels
    Kazuhiro Nakaya
    Cellular Biophysics Laboratory, Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506 5802, USA
    Am J Physiol Renal Physiol 292:F1314-21. 2007
    ....
  10. pmc Macrophage invasion contributes to degeneration of stria vascularis in Pendred syndrome mouse model
    Sairam V Jabba
    Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA
    BMC Med 4:37. 2006
    ..Here we determine the time course of hyperpigmentation and marginal cell disorganization, and test the hypothesis that inflammation contributes to this tissue degeneration...
  11. pmc Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential
    Philine Wangemann
    Anatomy and Physiology Department, 205 Coles Hall, Kansas State University, Manhattan, 66506, USA
    J Physiol 576:11-21. 2006
    ..It covers cochlear fluid composition, the generation of the endocochlear potential, K(+) secretion and cycling and its regulation, the role of gap junctions, mechanisms of acid-base homeostasis, and Ca(2+) transport...
  12. pmc Microarray-based comparison of three amplification methods for nanogram amounts of total RNA
    Ruchira Singh
    Dept of Anatomy and Physiology, College of Veterinary Medicine, Kansas State Univ, 1600 Denison Ave, Coles Hall 205, Manhattan, KS 66506, USA
    Am J Physiol Cell Physiol 288:C1179-89. 2005
    ..3 ng of total RNA. In addition, RS and pRS were faster and simpler to use than the T7-based methods and resulted in the generation of cDNA, which is more stable than cRNA...