The goal of this project is to characterize stem cells in the mammalian inner ear. The mammalian inner ear is unable to replace sensory hair cells lost due to damage or the long-term effects of age. Despite the considerable interest in the possibility of hair cell regeneration in mammals, virtually nothing is known concerning the identity and properties of the progenitors of sensory hair cells in the mammalian inner ear, nor whether any cells in the inner ear have the properties of stem cells. We have developed a novel cell culture system in which dissociated cells from the embryonic mouse inner ear can divide and generate hair cells, supporting cells and neurons over several weeks in culture. We will use this system to achieve the following Specific Aims. ? First, we will address whether single progenitor cells in the ear are multipotent and can give rise to hair cells, supporting cells and neurons, or whether they are more restricted and give rise to only a subset of these cell types. We will also test whether the developmental potential of these progenitor cells changes with time. Second, we will test whether the progenitor cells in our cultures have the extensive self-renewal capacity characteristic of true stem cells. Last, we will attempt to understand the mechanism by which Bone Morphogenetic Protein 4 (BMP-4) is able to influence multipotent progenitor cell fates in the inner ear. Our preliminary evidence suggests this growth factor causes a fivefold increase in hair cell production in cultures of inner ear epithelium. We will use both the addition of exogenous growth factors and cell-autonomous activation or repression of the BMP-4 signaling pathway to determine whether BMP-4 acts directly or indirectly, and instructively or selectively on sensory hair cell progenitors to promote hair cell differentiation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006185-02
Application #
6747329
Study Section
Special Emphasis Panel (ZDC1-SRB-J (11))
Program Officer
Freeman, Nancy
Project Start
2003-05-15
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$364,500
Indirect Cost
Name
House Ear Institute
Department
Type
DUNS #
062076989
City
Los Angeles
State
CA
Country
United States
Zip Code
90057
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Gu, Rende; Brown 2nd, Rogers M; Hsu, Chih-Wei et al. (2016) Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti. Dev Biol 414:72-84
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Basch, Martin L; Brown 2nd, Rogers M; Jen, Hsin-I et al. (2016) Fine-tuning of Notch signaling sets the boundary of the organ of Corti and establishes sensory cell fates. Elife 5:
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Maass, Juan C; Gu, Rende; Basch, Martin L et al. (2015) Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea. Front Cell Neurosci 9:110
Moayedi, Yalda; Basch, Martin L; Pacheco, Natasha L et al. (2014) The candidate splicing factor Sfswap regulates growth and patterning of inner ear sensory organs. PLoS Genet 10:e1004055

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