The organ of Corti in the inner ear converts the mechanical force arising from sound waves into electrical signals to inform the central nervous system. To accomplish this task, hair cells and supporting cells in the organ of Corti need complex and sophisticated protein networks to perform their functions. Discovering the individual proteins and their roles in the protein networks of the organ of Corti will enrich our understanding of normal and impaired cochlear physiology. The goal of the proposed work is to determine functions of two newly identified proteins: CEACAM16 and Marshalin. CEACAM16 is a cell adhesion protein that we discovered in the cochlea.
In AIM I, we propose to investigate functional roles of CEACAM16 for maintaining the tectorial membrane integrity and the connections between outer hair cells and the tectorial membrane. We will also investigate its relation to the DFNA4 deafness locus in both in vitro and in vivo environments. Marshalin is a microtubule-minus-end binding protein that we identified as a potential CDH23-associated protein.
In AIM II, we will examine Marshalin expression patterns in the organ of Corti and investigate Marshalin's function in both hair cells and supporting cells during cochlear development. We'll determine the molecular basis of interactions between Marshalin and its potential associated proteins including CDH23, actin, myosin 7a and spectrin. The investigation will provide much-needed information regarding Marshalin's roles in cross-linking actin filaments and MT filaments during hair cells and supporting cells differentiation, as well as Marshalin's connection with deafness locus DFNB15, one of earliest identified deafness loci. The investigation will also offer further information regarding CDH23 role for stereocilia formation. Various cellular, biochemical and electrophysiological methods, knockout and knockin mouse models, as well as in vivo physiology methods will be used to pursue our goals. The conclusions derived from the proposed work will not only allow the possible identification of new deafness genes, but will also provide the foundation for further understanding of formation of the organ of Corti. Such knowledge is sorely needed to understand many fundamental biological questions that are directly relevant to the molecular bases of normal and disordered communication processes.

Public Health Relevance

The goals of this proposal are to investigate two potential deafness-associated genes that play important roles in hearing. Aside from its intrinsic importance in auditory physiology, data collected from these studies will allow us to further recognize deafness-related genes and to manipulate their function for therapeutic purposes, either through molecular biological strategies, pharmacological treatments, and/or gene therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC011813-04
Application #
8829224
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
4
Fiscal Year
2015
Total Cost
$325,029
Indirect Cost
$114,654
Name
Northwestern University at Chicago
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Takahashi, Satoe; Sun, Willy; Zhou, Yingjie et al. (2018) Prestin Contributes to Membrane Compartmentalization and Is Required for Normal Innervation of Outer Hair Cells. Front Cell Neurosci 12:211
Takahashi, Satoe; Homma, Kazuaki; Zhou, Yingjie et al. (2016) Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-?-cyclodextrine is prestin-dependent. Sci Rep 6:21973
Takahashi, Satoe; Cheatham, Mary Ann; Zheng, Jing et al. (2016) The R130S mutation significantly affects the function of prestin, the outer hair cell motor protein. J Mol Med (Berl) 94:1053-62
Takahashi, Satoe; Mui, Vincent J; Rosenberg, Samuel K et al. (2016) Cadherin 23-C Regulates Microtubule Networks by Modifying CAMSAP3's Function. Sci Rep 6:28706
Cheatham, Mary Ann; Edge, Roxanne M; Homma, Kazuaki et al. (2015) Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice. PLoS One 10:e0145428
Cheatham, Mary Ann; Goodyear, Richard J; Homma, Kazuaki et al. (2014) Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus-frequency, and transiently evoked otoacoustic emissions. J Neurosci 34:10325-38
Keller, Jacob Pearson; Homma, Kazuaki; Duan, Chongwen et al. (2014) Functional regulation of the SLC26-family protein prestin by calcium/calmodulin. J Neurosci 34:1325-32
Wong, Patrick C M; Ettlinger, Marc; Zheng, Jing (2013) Linguistic grammar learning and DRD2-TAQ-IA polymorphism. PLoS One 8:e64983
Homma, Kazuaki; Duan, Chongwen; Zheng, Jing et al. (2013) The V499G/Y501H mutation impairs fast motor kinetics of prestin and has significance for defining functional independence of individual prestin subunits. J Biol Chem 288:2452-63
Zheng, Jing; Furness, David; Duan, Chongwen et al. (2013) Marshalin, a microtubule minus-end binding protein, regulates cytoskeletal structure in the organ of Corti. Biol Open 2:1192-202

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