MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS

描述（由申请人提供）：总体，长期目标的 在本申请中提出的研究是确定解剖学和 先天性周围性听力异常的生理基础 甲状腺功能减退症，并开始调查的分子性质， 相关赤字。通过这样做，我们希望扩大我们对 甲状腺激素在内耳正常发育中的作用， 我们对甲状腺功能减退的听觉后果的理解， 离散内耳组织和结构的相对贡献 在疾病的发病机制中。Tshrhyt突变小鼠非常适合 以满足拟议研究的需要，并将作为主要模型 甲状腺功能减退症的研究。我们还建议研究正常BALB/c 通过抗甲状腺药物的作用使小鼠甲状腺功能减退， 丙基硫氧嘧啶（PTU）和甲巯咪唑（MMI），以建立模型 甲状腺功能减退症引起的耳病理学， 文献中关于甲状腺激素作用的报道差异 听觉周围的缺陷，以及甲状腺的能力 激素来恢复患病动物的功能。 在这项提议中，主要的假设是异常的耳蜗 放大代表了甲状腺功能减退症诱导的 耳病理学和正常的被动转导是后天发育 在一个漫长的时间过程中。在这方面，除了实验之外， 旨在直接使用体内记录来解决主要问题 (ABR，CM和DPOAE），以及体外记录外毛细胞，我们 计划研究覆膜的形态和功能特性， 膜，沿着与其化学成分，以确定其作用， 疾病的发病机制。转导的其他被动方面的作用 (e.g.,耳蜗内电位）将被直接评估。我们还计划采取 这是研究的第一步，目的是确定分子和遗传基础， 应用RT-PCR和原位杂交技术， 可能影响耳蜗表达的转录本的表达 放大最后，我们建议探索一种有趣的可能性， 传出OC系统可能影响外周听觉的发育 功能如果这里提出的主要假设得到肯定，现有的模型 甲状腺功能减退症引起的听觉系统病理学将从根本上 修订。

DESCRIPTION (provided by applicant): The overall, long-term goal of the research proposed in this application is to determine the anatomical and physiological basis of peripheral auditory anomalies associated with congenital hypothyroidism and to initiate an investigation into the molecular nature of associated deficits. In doing so, we hope to expand our understanding of thyroid hormone's role in the normal development of the inner ear and extend our understanding of the auditory consequences of hypothyroidism by considering the relative contribution that discrete inner ear tissues and structures make in the pathogenesis of the disease. The Tshrhyt mutant mouse is ideally suited to meet the needs of the proposed research and will serve as the primary model of hypothyroidism in the proposed study. We also propose to study normal BALB/c mice rendered hypothyroid through the actions of the anti-thyroid drugs, propylthiouracil (PTU) and methimazole (MMI), in an effort to establish a model of hypothyroidism-induced otopathology that will allow us to clarify differences reported in the literature regarding the effects of thyroid hormone deficiency on the auditory periphery, as well as the capacity of thyroid hormone to restore function in diseased animals. The chief hypothesis being tested in this proposal is that abnormal cochlear amplification represents an enduring defect of hypothyroidism-induced otopathology and that normal passive transduction is acquired developmentally over a protracted time course. In that context, in addition to experiments designed to address the primary question directly using in vivo recordings (ABR, CM and DPOAE), as well as in vitro recordings from outer hair cells, we plan to study the morphological and the functional properties of the tectorial membrane, along with its chemical composition, to determine its role in the pathogenesis of the disease. The role of other passive aspects of transduction (e.g., endocochlear potential) will be assessed directly. We also plan to take the first step in a study aimed at determining the molecular and genetic basis of hypothyroidism, using RT-PCR and in situ hybridization to study the expression of transcripts that may affect the expression of cochlear amplification. Finally, we propose to explore the intriguing possibility that the efferent OC system may influence the development of peripheral auditory function. If the main hypotheses proposed here are affirmed, the existing model of auditory system pathology induced by hypothyroidism will be fundamentally revised.