Excess thyroid hormone induces a unique form of cardiac hypertrophy characterized by enhanced myocardial performance which may be related to switching from a low ATPase form of myosin to one with higher ATPase activity. At present our laboratory is attempting to define the mechanism(s) by which thyroid hormone regulates myosin isoenzyme expression. Although we mainly are concerned with the process of myosin isoform switching, we are impressed with the lack of information about nuclear thyroid hormone binding proteins themselves. Accordingly, the major aim of the proposed research is to investigate the role of nuclear T3 receptor in the initiation of cardiac hypertrophy and in the control of myosin isoenzymes expression. To accomplish these objectives, we plan, first, to clone the cDNA coding for the T3 receptor protein by using polyclonal and monoclonal antibodies to identify cDNAs coding for this protein in a specially constructed Lambdagt11 expression clone bank. Secondly, we propose to identify specific nuclear DNA binding sites for the T3 receptor. We have developed a strategy for isolation of the T3 receptor with its DNA fragment attached and support is requested to clone and sequence these fragments. These results should provide significant new information related to the structure of the T3 receptor protein and its DNA binding sites. These investigations will be carried out by a collaboration between Dr. Morkin's group in Tucson and Dr. Keith Latham's laboratory at the Uniformed Services University of the Health Sciences in Washington, D.C. Dr. Latham recently has developed polyclonal and monoclonal antibodies to the receptor protein. We believe the team we have assembled can make significant progress on elucidation of the mechanism of thyroid hormone actions on the heart and in other tissues.
