The long-term goal of my laboratory is to elucidate the mechanisms that control mechanotranduction in hair cells, and the defects in this process that cause deafness. We propose her 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) functionally 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 #
2R01DC005965-11
Application #
8630223
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2003-04-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
11
Fiscal Year
2014
Total Cost
$631,046
Indirect Cost
$298,040
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Webb, Stuart W; Grillet, Nicolas; Andrade, Leonardo R et al. (2011) Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain. Development 138:1607-17
Lelli, Andrea; Kazmierczak, Piotr; Kawashima, Yoshiyuki et al. (2010) Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15. J Neurosci 30:11259-69
Schwander, Martin; Kachar, Bechara; Müller, Ulrich (2010) Review series: The cell biology of hearing. J Cell Biol 190:9-20
Elledge, Heather M; Kazmierczak, Piotr; Clark, Peter et al. (2010) Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members. Proc Natl Acad Sci U S A 107:10708-12
Gillespie, Peter G; Muller, Ulrich (2009) Mechanotransduction by hair cells: models, molecules, and mechanisms. Cell 139:33-44
Grillet, Nicolas; Xiong, Wei; Reynolds, Anna et al. (2009) Harmonin mutations cause mechanotransduction defects in cochlear hair cells. Neuron 62:375-87
Schwander, Martin; Lopes, Vanda; Sczaniecka, Anna et al. (2009) A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells. J Neurosci 29:15810-8

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