MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS

描述(由申请人提供)：总体的、长期的目标 在这项申请中提出的研究是确定解剖学和 先天性外周听觉异常的生理基础 甲状腺功能减退症，并启动一项关于 相关的赤字。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和伸展中的作用 我们对甲状腺功能减退症听觉后果的认识 不连续的内耳组织和结构的相对贡献 在疾病的发病机制中起着重要作用。Tshhyt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 在这项拟议的研究中发现了甲状腺功能减退症。我们还建议研究正常的BALB/c 通过抗甲状腺药物的作用而导致甲状腺功能减退的小鼠， 丙基硫氧嘧啶(PTU)和他巴唑(MMI)，以建立模型 甲状腺功能减退症引起的耳部病理，将使我们能够澄清 文献报道的关于甲状腺激素影响的差异 听力外周缺陷，以及甲状腺功能障碍 恢复患病动物功能的荷尔蒙。 在这项建议中检验的主要假设是，异常耳蜗管 扩增是甲状腺功能减退症的持久缺陷 耳病理学和正常的被动转导是在发育过程中获得的 在一个漫长的时间进程中。在这方面，除了实验之外， 旨在利用活体录音直接解决主要问题 (ABR，CM和DPOAE)，以及外毛细胞的体外记录，我们 计划研究覆盖物的形态和功能特性 膜及其化学成分，以确定其在 疾病的发病机制。转导的其他被动方面的作用 (例如，耳蜗内电位)将直接进行评估。我们还计划采取 旨在确定分子和遗传基础的研究的第一步 应用逆转录聚合酶链式反应(RT-PCR)和原位杂交技术研究 转录本的表达可能影响耳蜗的表达 放大。最后，我们建议探索耐人寻味的可能性 传出的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 由甲状腺功能减退症引起的听觉系统病理改变将从根本上 已修订。

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.