MURINE MODELS OF HYPOTHYROIDISM AND CONGENITAL DEAFNESS

甲状腺功能减退症和先天性耳聋的小鼠模型

• 批准号: 6654502
• 负责人: Edward J Walsh
• 金额: $ 32.76万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-24 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654502
• 关键词: cell population study; cochlea; cochlear microphonic potentials; congenital deafness; developmental neurobiology; disease /disorder model; ear hair cell; electron microscopy; gene expression; genetically modified animals; hearing tests; histology; hormone regulation /control mechanism; hypothyroidism; in situ hybridization; laboratory mouse; model design /development; morphometry; neuroanatomy; neurons; otoacoustic emission; pathologic process; polymerase chain reaction; single cell analysis; thyrotropin; vertebrate embryology

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.

描述（申请人提供）： 本应用程序提出的研究是为了确定解剖学和 与先天性相关的外围听觉异常的生理基础 甲状腺功能减退症，并开始研究 相关的赤字。在这样做的过程中，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并延伸 我们通过考虑甲状腺功能减退症的听觉后果的理解 分离内耳组织和结构的相对贡献使得 在疾病的发病机理中。 TSHRHYT突变小鼠非常适合 满足拟议研究的需求，并将作为主要模型 拟议研究中甲状腺功能减退症。我们还建议研究正常的BALB/C 小鼠通过抗甲状腺药物的作用使甲状腺功能减退， 丙酸丙酸酯（PTU）和甲咪唑（MMI），以建立模型 甲状腺功能减退症引起的眼科病理学，这将使我们能够澄清 文献中报道的有关甲状腺激素的作用的差异 听觉外围的缺乏以及甲状腺的能力 激素以恢复患病动物的功能。 在该提议中检验的主要假设是异常人工耳蜗 扩增代表甲状腺功能减退症诱导的持久缺陷 眼科病理学和正常的被动转导将在发育中获得 在旷日持久的时间课程中。在这种情况下，除了实验 旨在直接使用体内录音来解决主要问题 （ABR，CM和DPOAE）以及外毛细胞的体外记录，我们 计划研究teTecorial的形态学和功能特性 膜以及其化学成分，以确定其在 疾病的发病机理。其他被动方面的作用 （例如，内核潜力）将直接评估。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 甲状腺功能减退症，使用RT-PCR和原位杂交研究 可能影响人工耳蜗表达的转录本的表达 放大。最后，我们建议探索有趣的可能性 传出的OC系统可能会影响外围听觉的发展 功能。如果确认这里提出的主要假设，则现有模型 甲状腺功能减退症引起的听觉系统病理学将是从根本上 修改。