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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035751-03
Application #
3349978
Study Section
(SRC)
Project Start
1985-09-30
Project End
1988-09-29
Budget Start
1987-09-30
Budget End
1988-09-29
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Markham, B E; Tsika, R W; Bahl, J J et al. (1990) An anti-sense c-erbA clone inhibits thyroid hormone-induced expression from the alpha-myosin heavy chain promoter. J Biol Chem 265:6489-93
Gustafson, T A; Markham, B E; Bahl, J J et al. (1987) Thyroid hormone regulates expression of a transfected alpha-myosin heavy-chain fusion gene in fetal heart cells. Proc Natl Acad Sci U S A 84:3122-6
Morkin, E (1987) Chronic adaptations in contractile proteins: genetic regulation. Annu Rev Physiol 49:545-54
Markham, B E; Bahl, J J; Gustafson, T A et al. (1987) Interaction of a protein factor within a thyroid hormone-sensitive region of rat alpha-myosin heavy chain gene. J Biol Chem 262:12856-62
Trent, J M; Flink, I L; Morkin, E et al. (1987) Localization of the human thyroxine-binding globulin gene to the long arm of the X chromosome (Xq21-22). Am J Hum Genet 41:428-35
Flink, I L; Bailey, T J; Gustafson, T A et al. (1986) Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases. Proc Natl Acad Sci U S A 83:7708-12