Deiodinases in Thyroid Hormone Homeostasis

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DESCRIPTION (provided by applicant): The types 1 and 2 iodothyroinine deiodinases (D1 and D2) are the enzymes which convert the prohormone T4 to the active hormone, T3. The Dio1 gene of humans and mice is highly stimulated by T3, inappropriately enhancing the severity of thyrotoxicosis of the hyperthyroid patient. D1 activity is also used as an index of peripheral thyroid status in transgenic animal models, but nothing is known as to why it is so T3 responsive. There are several genetic models in which the activities of D1 or D2 are reduced or absent. The C3H mouse adapts to a genetic decrease in D1 by increasing T4 to maintain a normal T3 and TSH. The D2 "knockout" mouse (D2KO) also has an elevated serum T4, and a normal T3, but an increased TSH. Surprisingly, these mice also have increased D1 suggesting peripheral compensation has occurred. Similar changes occur in chimeric mice produced by crossing the D2KO and C3H strains. Thus, despite seemingly normal T3 levels, at least one peripheral marker of thyroid status, D1 activity, suggests hyperthyroidism in the latter two mouse models. We hypothesize that increased D1 expression is one of the adaptive mechanisms allowing these animals to compensate for their resistance to T4, but it is not clear how this develops. In Aim I we will define the peripheral thyroid status of mice with impaired T4 activation and determine whether D1 is a reliable peripheral thyroid status marker. Physiological (02 consumption, bone density, growth) and biological ( the levels of T3 responsive mRNAs in various tissues) parameters will define the thyroid status. T4 infusion studies will reveal how the adaptation to the impaired T4 to T3 conversion occurs. The second Aim is to determine the molecular mechanism of the exquisite sensitivity of the Diol gene to T3. Various molecular techniques will elucidate the role of the thyroid response element we have identified in the Diol gene, and determine how it confers such a high T3 response. These studies will define factors increasing T4 to T3 conversion and elucidate how T3 continues to stimulate gene expression even in the hyperthyroid state. Employing these physiological approaches to assess the thyroid status of these mice will aid the candidate in pursing her short-term goal of gaining a solid background working with in vivo models to complement her molecular biological skills. This experience will help her achieve her long-term goal of becoming an independent biomedical scientist.