Cytosolic regulation of inner ear ion transport

Kansas State University, Manhattan KS

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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,