THYROID/RETINOID EFFECTS OF COCHLEAR DEVELOPMENT

耳蜗器的发育和Corti器的形成是一个 阐述了细胞命运和细胞发育调控的例子 差异化。甲状腺和维甲酸激素对 耳蜗体与胚胎耳廓的分化 普洛伊德。过量维甲酸的存在会导致血管畸形 成熟的耳蜗虫。甲状腺激素缺乏导致延迟和 不完全分化的器官的细胞成分 科尔蒂。甲状腺激素和维甲酸激素的分子作用是 通过它们与特定的核受体和 胞浆结合蛋白。核受体负责 对基因的调节，这些基因反过来负责发育和 耳蜗体的分化。这项研究的长期目标是 了解甲状腺和类维A酸所需的过程。 甲状腺功能正常发育及其过剩或不足的机制 荷尔蒙结果我改变了发育。在蒙古沙土鼠耳蜗里 细胞分化与成人听觉生理学研究进展 (听力)发生在产后时期。这种动物特别是 对成人听觉生理习得的研究有一定的参考价值。这个 该提案的三个具体目标是：1)分析时机和 甲状腺激素和维甲酸受体表达的细胞定位 在沙土鼠耳蜗的发育过程中。沙鼠受体将 用聚合酶链式反应进行克隆，并用定量逆转录聚合酶链式反应和 与胚胎和出生后动物的耳蜗进行原位杂交。 2)检测受体的形态和生理效应 体内产前激素治疗和体外后激素治疗激活 活体胎儿期受体激活对出生器官的影响 激素治疗与体外生后器官型人工耳蜗术 文化。怀孕的动物将接受过量的维甲酸治疗， 甲状腺激素和抗甲状腺药物。胚胎和胚胎的耳蜗线 将对出生后的动物进行形态和耳蜗器的检查 由体内和体外电生理学测定的生理学 化验。3)评价甲状腺的生化和细胞生物学效应。 以及维甲酸激素治疗对耳蜗发育的影响。的影响 甲状腺和维甲酸激素的治疗将在开发中进行检查 甲状腺和视黄醇表达的变化 受体，~3H-胸腺嘧啶核苷标记的细胞增殖模式， 细胞凋亡的末端转移酶标记模式。了解以下内容 这两种激素系统是如何影响耳道发育的 深入了解耳蜗机能习得的机制。今年5月 此外，还提供了对听觉功能障碍的洞察， 可能导致药物或基因疗法的发展 用于先天和后天人类听力障碍。

Cochlear development and the formation of the organ of Corti is an elaborate example of the developmental regulation of cellular fate and differentiation. Thyroid and retinoid hormones have profound effects on the differentiation of the cochlea from the rudimentary embryonic otic placode. The presence of excess retinoic acid results in malformation of the mature cochlea. Deficiency of thyroid hormone results in delayed and incomplete differentiation of the cellular components of the organ of Corti. The molecular actions of thyroid and retinoid hormones are accomplished by their interaction with specific nuclear receptors and cytosolic binding proteins. The nuclear receptors are responsible for regulation of genes which are in turn responsible for the development and differentiation of the cochlea. The long-term goal of this study is to understand the processes for which thyroid and retinoids are required in normal development and the mechanisms by which excess or deficiency of thee hormones results i altered development. In the mongolian gerbil cochlear cellular differentiation and the achievement of adult auditory physiology (hearing) occurs in the post-natal period. The animal is particularly useful for the study of the acquisition of adult auditory physiology. The three specific aims of the proposal are; 1) To analyze the timing and cellular localization of thyroid hormone and retinoid receptor expression during development of the cochlea in the gerbil. The gerbil receptors will be cloned by PCR and receptor expression studied by quantitative RT-PCR and in situ hybridization with cochlea from embryonic and post-natal animals. 2) To examine the morphologic and physiologic effects of receptor activation with in vivo prenatal hormone treatment and with in vitro post- natal organotypic effects of receptor activation with in vivo prenatal hormone treatment and with in vitro post-natal organotypic cochlear cultures. Pregnant animals will be treated with excess retinoic acid, thyroid hormone, and antithyroid drugs. The cochlea of embryonic and postnatal animals will be examined morphologically and the cochlear organ physiology determined by both in vivo and in vitro electrophysiologic assays. 3) To assess the biochemical and cell biologic effects of thyroid and retinoid hormone treatments on cochlear development. The effects of thyroid and retinoid hormone treatment will be examined in developing cochlea by examining; the alteration in expression of thyroid and retinoid receptors, the 3H-thymidine labeling pattern of cellular proliferation, the terminal transferase labeling pattern of cellular apoptosis. Knowledge of how these two hormone systems influence otic development should provide insight into the mechanisms of acquisition of cochlear function. This may additionally provide insight into disorders of auditory function, which could lead to the development of pharmacologic or gene therapy treatments for congenital and acquired human hearing disorders.