Our ability to manipulate gene expression specifically in the hair cells of the inner ear during development and adulthood in mice is crucial for understanding the physiology of hearing and the pathology of deafness in humans. Recent advances from our laboratory and many others have demonstrated that gene expression can be manipulated in developing mouse hair cells in a spatially and temporally controlled manner. However, a key feature remains elusive -- our ability to manipulate gene expression specifically in mature inner hair cells (IHCs) and outer hair cells (OHCs). Here we propose to develop transgenic or knockin mice that express inducible CreERT2, an effective fusion of Cre and estrogen receptor (CreER), in mature cochlear hair cells (OHCs in Aim 1; IHCs and OHCs in Aim 2). The characterization and availability of these mouse lines will enable auditory researchers to inactivate or activate genes of their interest in mature hair cells. The creation of conditional (loxP) alleles of every mouse gene in their genome, which has been proposed in the NIH's Knockout Mouse Project (KOMP), will provide a complementary resource for the use of the inducible Cre lines that we generate. Finally, the strategies we adopt here can be used to express genes specifically in other mature cell types of the inner ear (i.e., IHCs, spiral ganglia, stria fibrocytes and marginal cells) at any given time. All mouse lines will be genetically engineered in 129S7/C57BL/6J mixed or FVB/NJ strains, transferred to the CBA/CaJ strain, and then deposited in the NIH-sponsored Mutant Mouse Regional Resource Center (MMRRC). Public Health Relevance Statement An estimated 28 million people in the United States are deaf or hard of hearing. Approximately 1.5 million individuals aged 3 years or older are deaf in both ears and 2 to 3 per 1,000 live births suffer congenital hearing loss. More than 40 million persons in the United States suffer various levels of noise induced hearing loss. Despite the significant progress in our understanding of these hearing disorders, very little is known about the disease causes and about the normal hearing processes in adults. Many genetic factors (genes) that, when mutated, cause hearing impairment in people, play critical roles in both infants and adults. We propose here to develop genetic tools that would allow us to investigate the function of hearing related genes in adult animal models. These tools will be able to surgically activate genes in a specific set of cells in the hearing process at any time of the adult life of the animal. This temporal and spatial precision is critical for our understanding of hearing process and developing therapeutic targets for intervention of the hearing disorders. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC008800-02
Application #
7352736
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2007-02-10
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$222,075
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Liu, Zhiyong; Fang, Jie; Dearman, Jennifer et al. (2014) In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression. PLoS One 9:e89377
Cox, Brandon C; Chai, Renjie; Lenoir, Anne et al. (2014) Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141:816-29
Mellado Lagarde, Marcia M; Cox, Brandon C; Fang, Jie et al. (2013) Selective ablation of pillar and deiters' cells severely affects cochlear postnatal development and hearing in mice. J Neurosci 33:1564-76
Layman, Wanda S; Sauceda, Mario A; Zuo, Jian (2013) Epigenetic alterations by NuRD and PRC2 in the neonatal mouse cochlea. Hear Res 304:167-78
Cox, Brandon C; Liu, Zhiyong; Lagarde, Marcia M Mellado et al. (2012) Conditional gene expression in the mouse inner ear using Cre-loxP. J Assoc Res Otolaryngol 13:295-322
Liu, Zhiyong; Owen, Thomas; Fang, Jie et al. (2012) Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner. PLoS One 7:e34123
Fang, Jie; Zhang, Wen-Cheng; Yamashita, Tetsuji et al. (2012) Outer hair cell-specific prestin-CreERT2 knockin mouse lines. Genesis 50:124-31
Yamashita, Tetsuji; Fang, Jie; Gao, Jiangang et al. (2012) Normal hearing sensitivity at low-to-middle frequencies with 34% prestin-charge density. PLoS One 7:e45453
Kurt, Simone; Sausbier, Matthias; Ruttiger, Lukas et al. (2012) Critical role for cochlear hair cell BK channels for coding the temporal structure and dynamic range of auditory information for central auditory processing. FASEB J 26:3834-43
Liu, Zhiyong; Walters, Brandon J; Owen, Thomas et al. (2012) Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium. J Neurosci 32:10530-40

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