Abstract

Thyroid hormone (T3) and its two receptors (TRa and TR ) are essential for the development of the auditory system. This proposal will correlate specific cellular and physiological processes in auditory development with defined transcriptional pathways from a given TR variant to its downstream target genes to determine the extent to which TRa and TR mediate unique or uncooperative functions. The auditory defect in TR-deficient mice will be investigated morphologically and functionally, focusing on the cochlea as the primary T3-sensitive site in the auditory system. These studies are designed to enhance our understanding of the role of T3 and TR genes in auditory development and function.
These specific aims as listed in the proposal are: (1) To investigate the cellular and physiological functions of TR in cochlear development; (2) To investigate the function and expression of TR 2 in the cochlea by targeted mutagenesis of a TR 2-specific exon; (3) To determine the individual and combined functions of TR and TR[alpha]; (4) To investigate ligand availability in the developing cochlea; (5) To investigate TR-dependent transcriptional pathways (to isolate and characterize target genes).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003441-05
Application #
6379399
Study Section
Hearing Research Study Section (HAR)
Program Officer
Watson, Bracie
Project Start
1997-08-01
Project End
2002-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
5
Fiscal Year
2001
Total Cost
$272,241
Indirect Cost

  Institution

Name
Mount Sinai School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029

  Publications

Ng, Lily; Hernandez, Arturo; He, Wenxuan et al. (2009) A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 150:1952-60
Liu, Hong; Etter, Paige; Hayes, Susan et al. (2008) NeuroD1 regulates expression of thyroid hormone receptor 2 and cone opsins in the developing mouse retina. J Neurosci 28:749-56
Vasudevan, Nandini; Kia, Hosein Kami; Hadjimarkou, Maria et al. (2005) Retinoid-related receptor (ROR) alpha mRNA expression is altered in the brain of male mice lacking all ligand-binding thyroid hormone receptor (TR) isoforms. Endocrine 26:25-32
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
Kelley, Matthew W; Lanford, Pamela J; Jones, Iwan et al. (2003) Analysis of nuclear receptor function in the mouse auditory system. Methods Enzymol 364:426-48
Abel, E Dale; Moura, Egberto G; Ahima, Rexford S et al. (2003) Dominant inhibition of thyroid hormone action selectively in the pituitary of thyroid hormone receptor-beta null mice abolishes the regulation of thyrotropin by thyroid hormone. Mol Endocrinol 17:1767-76
Suzuki, H; Zhang, X-Y; Forrest, D et al. (2003) Marked potentiation of the dominant negative action of a mutant thyroid hormone receptor beta in mice by the ablation of one wild-type beta allele. Mol Endocrinol 17:895-907
Amma, Lori L; Goodyear, Richard; Faris, Jonathan S et al. (2003) An emilin family extracellular matrix protein identified in the cochlear basilar membrane. Mol Cell Neurosci 23:460-72
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
Tinnikov, Alexander; Nordstrom, Kristina; Thoren, Peter et al. (2002) Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. EMBO J 21:5079-87

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