THYROID HORMONE RECEPTORS AND GENETIC CONTROL OF HEARING

描述(申请人提供)：甲状腺激素对听力的发育是必不可少的，发育早期激素水平不足会导致严重耳聋。虽然对甲状腺激素的需求是众所周知的，但对它如何作用以及它在听觉系统发育中控制什么的了解较少。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一连串事件中的关键步骤。这些受体在听觉系统中的主要作用部位在耳蜗处。甲状腺激素受体作为激素激活的转录因子，由两个相关基因thrA和thrb编码。小鼠的靶向性突变表明Thrb在控制耳蜗发育中起主要作用，而Thrb起次要作用。这些突变的表型表明，甲状腺激素受体在听觉功能开始之前调节耳蜗相对较晚的成熟阶段。这一新的应用旨在通过研究以下方面来促进我们对这些受体在耳蜗发育中的作用的理解：1)甲状腺激素代谢酶(脱碘酶)作为甲状腺激素受体功能调节的作用；2)诱导Thrb基因在耳蜗中表达的发育信号；3)利用Thrb基因缺失的小鼠发现一个新的基因，以筛选与耳蜗成熟阶段相关的基因。该基因在耳蜗基底膜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.