THYROID/RETINOID EFFECTS OF COCHLEAR DEVELOPMENT

甲状腺/类维生素A对耳蜗发育的影响

• 批准号: 6104468
• 负责人: LAIRD D MADISON
• 金额: $ 16.47万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104468
• 关键词: apoptosis; autoradiography; behavioral /social science research tag; cell biology; cochlea; cochlear microphonic potentials; communication disorders; complementary DNA; gene expression; gerbil /jird; histogenesis; hormone receptor; hormone regulation /control mechanism; in situ hybridization; messenger RNA; newborn animals; polymerase chain reaction; protein isoforms; protein structure function; receptor expression; retinoid binding proteins; retinoids; sensory disorders; thyroid disorder; thyroid hormones; tissue /cell culture

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.

皮质发育和Corti器官的形成是一个重要的生物学过程。 细胞命运的发育调节的详细例子， 分化 甲状腺和类维生素A激素对 耳蜗与发育不全的胚胎耳的分化 基板 过量视黄酸的存在导致畸形， 成熟的耳蜗 甲状腺激素缺乏导致延迟和 器官细胞成分的不完全分化 科蒂 甲状腺激素和维甲酸激素的分子作用是 通过与特定核受体的相互作用完成， 胞质结合蛋白。 核受体负责 基因的调控反过来又负责发展， 耳蜗的分化。 这项研究的长期目标是 了解甲状腺和类维生素A的过程，需要在 正常的发展和机制，过度或缺乏你 荷尔蒙的结果是我改变了发育。 蒙古沙鼠耳蜗 细胞分化和成人听觉生理学的成就 （听力）发生在出生后。 动物特别是 这对成人听觉生理学的研究是有用的。 的 该提案的三个具体目标是：1）分析时间和 甲状腺激素和维甲酸受体表达的细胞定位 在沙鼠耳蜗的发育过程中。 沙鼠的感受器 通过PCR进行克隆，并通过定量RT-PCR研究受体表达， 胚胎和出生后动物耳蜗原位杂交。 2)检测受体的形态学和生理学效应 用体内产前激素处理和用体外后- 体内产前受体激活的纳塔尔器官型效应 激素治疗和体外出生后器官型耳蜗 cultures. 妊娠动物将用过量的视黄酸处理， 甲状腺激素和抗甲状腺药物。 胚胎期耳蜗和 将对出生后的动物进行形态学检查， 通过体内和体外电生理学确定的生理学 测定。 3)评估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 甲状腺和类维生素A激素治疗将在发展中国家进行检查。 甲状腺、维甲酸表达的变化 受体，细胞增殖的3 H-胸苷标记模式， 细胞凋亡的末端转移酶标记模式。 知识 这两种激素系统如何影响耳部发育， 深入了解耳蜗功能获得的机制。 这可能 此外，还可以深入了解听觉功能障碍， 可能导致药物或基因治疗的发展 先天性和后天性人类听力障碍的治疗。