THYROID HORMONE RECEPTORS AND GENETIC CONTROL OF HEARING

描述（由申请人提供）：甲状腺激素对听力发育至关重要，在发育早期激素水平不足会导致深度耳聋。虽然对甲状腺激素的需求是众所周知的，但对它在听觉系统发育中的作用和控制作用却知之甚少。靶组织中的甲状腺激素受体将激素信号传递到细胞反应中。因此，对这些受体的研究有望揭示控制听觉系统发育的事件链中的关键步骤。这些感受器在听觉系统中的主要作用部位是耳蜗。甲状腺激素受体是激素激活的转录因子，由Thra和Thrb两个相关基因编码。小鼠的靶向突变表明Thrb在耳蜗发育的控制中起主要作用，Thra在耳蜗发育的控制中起次要作用。突变表型表明，甲状腺激素受体调节相对较晚的耳蜗成熟阶段，在听觉功能开始之前。本研究旨在通过以下方面的研究，进一步了解这些受体在耳蜗发育中的作用：1)甲状腺激素代谢酶（去碘酶）在耳蜗中作为甲状腺激素受体功能调节因子的作用；2)诱导耳蜗Thrb基因表达的发育信号；3)利用Thrb-null小鼠筛选参与耳蜗发育成熟阶段的基因，发现了一个新的基因。该基因在耳蜗基底膜中表达一种新的细胞外基质蛋白。

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.