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.
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