THYROID HORMONE RECEPTORS AND GENETIC CONTROL OF HEARING

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DESCRIPTION (provided by applicant): 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.