Our overall goal remains the enhancement of understanding of the hierarchical mechanisms of control of thyroid hormone (TH) production, organ distribution and metabolism, action and excretion (integrated regulation of sources and sinks) in mammals. This includes responses of this neuroendocrine system to normal and abnormal perturbations. Our approach remains quantitative, global and integrative, with continuing emphasis on the enterohepatic system, particularly the role of intestinal components and processes in overall TH regulation in health and disease states. We shall explore the effects of disease and nutrition on whole- body and differential organ distribution, organ storage and local metabolism of T3, T4 and their potentially potent of prepotent acetic acid derivatives (Triac and Tetrac), in rats. We shall quantify sources, sinks and their interrelationships in different states, by applying our novel whole-body steady state experiment methodology to: (1) study the effects to fasting, meals, primary hypothyroidism, and intestinal abnormalities, including oral drugs and surgical interventions, on TH regulation; (2) measure whole-body interconversion rates of T4 to T3, T4 to Tetrac (T4A), Tetrac to Triac (T3A), T3 to T3A, which are implicated in hormone activating or preactivating processes; (3) measure the contribution of Type I 5'-deiodinase, the major hormone activator, in the production of T3 and T3A; (4) measure true local tissue production rates of T3 from T4 in liver, brain, kidneys, intestines and other T3-producing organs in vivo; (5) measure the true glandular T3 secretion rate and true total body T3 production rate and total body and organ pool sizes in each of the above states.
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