REGULATION OF THYROID FUNCTION--T4 AND T3 KINETICS

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Thyroid hormones are essential for good health and are also critically important for fetal and neonatal brain development. They are secreted in two forms, (T4) and 3,5,3'-triiodothyronine (T3). T3 regulates the transcription of many genes. T4, in contrast, is essentially inactive for genomic processes unless converted to T3. This process, termed peripheral conversion, is controlled by at least two distinct enzymes, the Type I and the Type II 5'-deiodinases (5'D-I and 5'D-II). Primary thyroid dysfunction is the major cause of thyroid insufficiency and thyroid hormone excess. it is now apparent that peripheral deiodination of T4 to generate T3 plays a major role not only in regulating the overall supply of T3 but also in selectively modulating T3 concentrations within distinct Organs. Two recent discoveries have focused renewed attention on the extrathyroidal events regulating the availability of thyroid hormones to peripheral tissues. First, 5'D-I, considered to be the major enzyme responsible for peripheral conversion to generate plasma T3 from secreted T4, is a selenium requiring enzyme. Second, transthyretin (TTR) in the cerebrospinal fluid, synthesized in the choroid plexus, constitutes a specialized system for transport of T4, but not T3, to the brain. The studies proposed in this grant will define the importance of the 5'D-I selenoprotein to the generation and clearance of plasma iodothyronines, particularly T3, and explore the consequences of selenium deficiency on neonatal thyroid homeostasis and thyroid hormone dependent brain maturation. We will also attempt to determine the contributions of de novo T3 synthesis and thyroid 5'D-deiodination of T4 to generate T3 to the overall secretion of T3 from the thyroid. These studies will use selenium deficiency, which impairs 5'D-I activity in liver and kidney but not in the thyroid, and an analog of PTU, which does not affect thyroid hormone synthesis but does inhibit 5'D-I activity in liver, kidney and thyroid. Studies will also be performed to establish the role of cerebrospinal fluid TTR in the transport and regulation of thyroid hormone dependent processes in the brain.