The long-term goal of my laboratory is to elucidate the mechanisms that control mechanotransduction in hair cells, and the defects in this process that cause deafness. We propose here to identify and study proteins that interact with PCDH15 and TMHS/ LHFPL5 (referred to in the following as LHFPL5), two components of the hair cell's mechanotransduction machinery. Based on preliminary data, we hypothesize that PCDH15 and LHFPL5 are components of a larger protein complex that regulates the activity of mechanically gated ion channels in hair cells. We predict that mutations in complex components lead to auditory impairment. To test our hypothesis, we will: (i) Determine the function of LHFPL5 and some of its close homologues for mechano-transduction and auditory perception; (ii) continue our identification of hair cell proteins that interact with PCDH15 and/or LHFPL5; (iii) functionall characterize proteins that interact with PCDH15 and/or LHFPL5; (iv) determine their relevance for auditory impairment in humans. Our preliminary data show the feasibility of our approach. We have already identified hair cell proteins that interact with PCDH15 and LHFPL5, at least one of which is linked to auditory impairment in humans.

Public Health Relevance

Hearing loss is a major health problem that significantly affects the life quality of affected individuals. Many forms of hearing loss are genetic in origin and affect hair cells, the mechanosensors that convert sound induced vibrations into electrical signals. We propose here to identify components of the mechanotransduction machinery of hair cells, and how mutations in the genes that encode these components lead to hearing loss, which we anticipate will ultimately lead to better treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005965-15
Application #
9173019
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2003-04-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
15
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Zhao, Bo; Wu, Zizhen; Müller, Ulrich (2016) Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function. Elife 5:
Zeng, Wei-Zheng; Grillet, Nicolas; Dewey, James B et al. (2016) Neuroplastin Isoform Np55 Is Expressed in the Stereocilia of Outer Hair Cells and Required for Normal Outer Hair Cell Function. J Neurosci 36:9201-16
Wu, Zizhen; Müller, Ulrich (2016) Molecular Identity of the Mechanotransduction Channel in Hair Cells: Not Quiet There Yet. J Neurosci 36:10927-10934
Beurg, Maryline; Xiong, Wei; Zhao, Bo et al. (2015) Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc Natl Acad Sci U S A 112:1589-94
Müller, Ulrich; Barr-Gillespie, Peter G (2015) New treatment options for hearing loss. Nat Rev Drug Discov 14:346-65
Zhao, Bo; Müller, Ulrich (2015) The elusive mechanotransduction machinery of hair cells. Curr Opin Neurobiol 34:172-9
Zhao, Bo; Wu, Zizhen; Grillet, Nicolas et al. (2014) TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84:954-67
Xiong, Wei; Wagner, Thomas; Yan, Linxuan et al. (2014) Using injectoporation to deliver genes to mechanosensory hair cells. Nat Protoc 9:2438-49
Kazmierczak, Piotr; Muller, Ulrich (2012) Sensing sound: molecules that orchestrate mechanotransduction by hair cells. Trends Neurosci 35:220-9
Xiong, Wei; Grillet, Nicolas; Elledge, Heather M et al. (2012) TMHS is an integral component of the mechanotransduction machinery of cochlear hair cells. Cell 151:1283-95

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