Usher syndrome (USH) represents the most prevalent form of inherited recessive deafness associated with blindness. In the inner ear, USH proteins constitute the components of stereocilia bundle and mechanoelectricaltransduction(MET)machinery.WehavepreviouslyidentifiedtheCIB2geneencoding Calcium and Integrin-Binding protein 2 (CIB2) as the cause of USH1 and non-syndromic deafness in diverse populations (Patel et al 2015, Riazuddin et al 2012, Seco et al 2016). CIB2 is expressed in the haircellstereociliainrodents,butitsexactfunctionwasunknown(Riazuddinetal2012).Intheprevious fundingperiod,wegeneratedamousemodelcarryingthehumandeafness-relatedCib2variant(Cib2F91S knock-in) and characterized it together with a mouse line lacking CIB2 (Cib2tm1a). We found that both thesemousestrainsaredeafandhavenoconventionalMETresponsesintheauditoryhaircells,despite thepresenceoftiplinksthatnormallygatetheMETchannelsandapparentlyunchangedlocalizationof mutantCIB2inthestereociliaofCib2F91S/F91Smice.WealsofoundthatCIB2bindstothecomponentsof thehaircellMETcomplex,TMC1andTMC2,andtheseinteractionsaredisruptedbydeafness-causing Cib2 variants. We concluded that CIB2 is essential for the MET function (Giese et al 2017). This novel elementoftheMETmachineryisparticularlyinterestingbecauseitmayberesponsibleforatleastsome ofthemultiplewell-knowneffectsofCa2+onthehaircellmechanotransduction.Here,wewillexplorethe exactroleofCIB2inMET.Towardsthisend,wehavealreadygeneratedanotherknock-inmousestrain (Cib2R186W).R186WvariantdoesnotaffectCIB2interactionwithTMC1/2butimpairsitscalciumbuffering ability. Cib2R186W mice will be compared with Cib2F91S allele that impairs CIB2 interaction with TMC1/2, leadingtothelossofMET.OurstudiesalsoestablishedthatCIB2deficiencyresultsinabnormalgrowth ofthetransducingshorterrowstereociliainthehairbundlewithoutaffectingnon-transducingtallestrow stereocilia (Giese et al 2017). Thus, CIB2 may represent an important molecule, linking MET channel activityandstereociliaactincoreremodeling.Theexistenceofsuchlinkwasestablishedinourparallel study(Velez-Ortegaetal2017).Here,wewilldeterminehowCIB2controlstheheightofthetransducing stereociliaintheauditoryhaircells.Finally,wehavealsofoundthatCIB2deficiencyresultsindecreased numberoftheinnerhaircell(IHC)synapses.Therefore,wewillinvestigatethepotentialmechanismsof CIB2 involvement in the IHC synaptic function. The expected outcomes of this study are to uncover (a) the precise mechanism of deafness associated with CIB2 deficiency and (b) the physiological role of CIB2 protein in hair cell functions, especially in MET and neurotransmission. The potential for positive impactisinherent;?decipheringthefunctionsofUSHproteinsisacriticalsteptowardsthedevelopmentof actualtherapiesforthetreatmentand/orpreventionofthisdebilitating,lifelongdisease.

Public Health Relevance

. Advancement in the understanding of molecular mechanisms of the inner ear is a prerequisitetodevelopingtherapeuticstrategiesforhearingimpairment.Thestudiesoutlinedinthisproposal seek to understand the general function of a calcium binding protein known as CIB2 and its associated pathophysiology due to mutations of CIB2 encoding this protein. Thus the proposed research is developing fundamentalknowledgethatwillhelptoreducetheburdenofhumanhearingloss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Watson, Bracie
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University of Maryland Baltimore
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