An extensive body of work establishes the role of protein-coding genes and their products in development of the ear and neurosensory function. In addition, recent advances in RNA biology have firmly established the importance of non-coding RNAs as regulatory molecules affecting developmental processes. MicroRNAs (miRNAs) represent a large class of small non-coding RNAs that function to repress the expression of complementary target genes. Certain miRNAs are demonstrated regulators of cellular proliferation, differentiation and fate specification that ultimately affect morphogenesis, histogenesis and organogenesis in a variety of organisms. Our published data has established the little that is known about the developmental expression patterns and biological functions of miRNAs in the mammalian ear. Our long-term objectives are to understand how miRNAs intersect ear biology by characterizing miRNA expression and function in the developing mouse inner ear, and to implement miRNA-based therapeutic strategies designed to maintain or restore cellular functions crucial to hearing. Our previous studies have revealed the complement of miRNAs expressed in the mouse inner ear and have demonstrated neurosensory cell- specific miRNA expression.
The specific aims of this current application seek to 1) characterize the expression patterns of miRNAs that are relevant to ear biology, 2) demonstrate the requirement of miRNAs in neurosensory epithelial development and maintenance, and 3) determine specific hair cell miRNA functions in development and maintenance. As therapeutic avenues for stimulating neurosensory cell regeneration and restoring hearing progress, they might benefit substantially from miRNA-based strategies that guide new cell populations toward normal neurosensory cell functions. A major cause of hearing loss and deafness is sensory cell death resulting from aging, infections, toxic drugs, or overstimulation. The proposed research will determine the roles of microRNA genes in normal ear development and sensory cell function. Understanding how these small RNAs influence such processes is expected to impact molecular therapeutic strategies designed to regenerate sensory cells and restoring hearing.

Public Health Relevance

A major cause of hearing loss and deafness is sensory cell death resulting from aging, infections, toxic drugs, or overstimulation. The proposed research will determine the roles of microRNA genes in normal ear development and sensory cell function. Understanding how these small RNAs influence such processes is expected to impact molecular therapeutic strategies designed to regenerate sensory cells and restoring hearing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009025-05
Application #
8514398
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2009-06-02
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$330,624
Indirect Cost
$91,208
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
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Zhang, Qian; Liu, Huizhan; McGee, Joann et al. (2013) Identifying microRNAs involved in degeneration of the organ of corti during age-related hearing loss. PLoS One 8:e62786
Kersigo, Jennifer; D'Angelo, Alex; Gray, Brian D et al. (2011) The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1-cre-mediated microRNA loss. Genesis 49:326-41
Weston, Michael D; Pierce, Marsha L; Jensen-Smith, Heather C et al. (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn 240:808-19