Inner ear hair cell loss and lack of hair cell regeneration are the major cause of permanent hearing loss. In this application, it is proposed to test whether mouse embryonic stem cell-generated hair cell- like cells are functional in the sense that they display mechanotranduction currents, appropriate basolateral currents, as well as the ability to form appropriate synaptic connections. It is further planned to develop an in utero cell-replacement treatment to determine correlation between occurrence of graft-derived hair cells and regionalized restoration of the organ of Corti. Physiologically, we expect that such a restoration may lead to alleviation of hair cell loss and hearing impairment in a mouse model.
A second Aim addresses the guidance of embryonic stem cells toward hair cell-like cells. It is proposed to devise a protocol of defined inductive steps, which will enable researchers to efficiently generate progenitor cells from embryonic stem cells that are competent to develop along the otic lineage.
A third Aim proposes to identify a non-FGF-based activity that is involved in otic induction, which is released from a region of the chicken embryo that is adjacent to the otic placode.

Public Health Relevance

Toward finding a treatment for hearing loss, it is proposed to continue research on converting mouse embryonic stem cells into hair cells. First, it is planned to assess whether stem cell-generated hair cell-like cells display the same functional properties as wild type hair cells, particularly cochlear hair cells. Building on this, it is planned to use embryonic stem cell-derived inner ear progenitor cells to treat a mouse model of hereditary deafness and to test whether hearing loss can be alleviated with a cellular treatment. In a parallel Aim, it is proposed to increase the efficacy by which embryonic stem cells can be "primed" to become responsive to inner ear inducing signals. This will be done by mimicking the inductive steps that lead to establishment of the inner ear during embryonic development. In the third Aim, it is planned to identify a signaling molecule from chicken embryonic tissue that appears to be conducting such a "priming", which makes progenitor or stem cells responsive to FGF-based inner ear inducing activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006167-10
Application #
8246480
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Freeman, Nancy
Project Start
2003-05-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$390,564
Indirect Cost
$134,041
Name
Stanford University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Volkenstein, Stefan; Oshima, Kazuo; Sinkkonen, Saku T et al. (2013) Transient, afferent input-dependent, postnatal niche for neural progenitor cells in the cochlear nucleus. Proc Natl Acad Sci U S A 110:14456-61
Jan, Taha Adnan; Chai, Renjie; Sayyid, Zahra Nabi et al. (2013) Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Development 140:1196-206
Ronaghi, Mohammad; Nasr, Marjan; Heller, Stefan (2012) Concise review: Inner ear stem cells--an oxymoron, but why? Stem Cells 30:69-74
Volkenstein, Stefan; Kirkwood, John E; Lai, Edwina et al. (2012) Oriented collagen as a potential cochlear implant electrode surface coating to achieve directed neurite outgrowth. Eur Arch Otorhinolaryngol 269:1111-6
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Oshima, Kazuo; Shin, Kunyoo; Diensthuber, Marc et al. (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141:704-16
Brigande, John V; Heller, Stefan (2009) Quo vadis, hair cell regeneration? Nat Neurosci 12:679-85

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