Thyroid hormone is essential for the development of hearing and inadequate hormone levels at early stages of development lead to profound deafness. Although the need for thyroid hormone is well known, less is understood of how it acts and what it controls in the development of the auditory system.Thyroid hormone receptors in target tissues transmit the hormonal signal into cellular responses. The study of these receptors is therefore expected to reveal critical steps in the chain of events that control the development of the auditory system. A primary site of action of these receptors in the auditory system is in the cochlea.Thyroid hormone receptors act as hormone-activated transcription factors and are encoded by two related genes, Thra and Thrb. Targeted mutagenesis in mice indicates that Thrb has the primary role and Thra a lesser role in the control of cochlear development. The mutant phenotypes indicate that thyroid hormone receptors regulate relatively late stages of maturation of the cochlea prior to the onset of auditory function.This renewal application aims to advance our understanding of the role of these receptors in cochlear -development by investigation of: 1) The role of thyroid hormone-metabolizing enzymes (deiodinases) as regulators of thyroid hormone receptor function in the cochlea; 2) The developmental signals that induce Thrb gene expression in the cochlea; 3) A novel gene that was identified using Thrb-null mice to screen for genes involved in the maturational stages of cochlear development. This gene expresses a novel extracellular matrix protein in the cochlear basilar membrane.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003441-07
Application #
6615559
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Watson, Bracie
Project Start
1997-08-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
7
Fiscal Year
2003
Total Cost
$347,051
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Ng, Lily; Goodyear, Richard J; Woods, Chad A et al. (2004) Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase. Proc Natl Acad Sci U S A 101:3474-9
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Oishi, Kimihiko; Hofmann, Susanna; Diaz, George A et al. (2002) Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet 11:2951-60
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