Na+, K+-activated adenosine triphosphatase (Na, K-ATPase) is a ubiquitous energy transducing integral plasma membrane protein whose activity is of critical importance to the normal function of virtually all animal cells. In the heart the enzyme represents the cellular receptor for digitalis glycosides and its abundance and activity is significantly stimulated by the action of thyroid hormone (T3). The stimulatory effect of T3 on energy metabolism of the heart in vivo is a consequence of the direct actions of the hormone on cardiac myocytes as well as the increase in cardiac contractile work (cardiac output. in response to enhanced energy demand by other tissues. It has also been noted that the heart in hyperthyroid humans and animals manifests a reduction in functional """"""""reserve"""""""" and maximal work capacity that is associated with a marked reduction in myocardial creatine-phosphocreatine pool. Such hearts are hence prone to fail if stimulated to work at or near maximal levels. The objectives of the proposed research program are two-fold. 1) To define the cellular and molecular mechanisms by which the abundance and activity of Na, K-ATPase is regulated in the myocardium, and 2) To define the role of thyroid hormone on myocardial creatine transport and metabolism, and to delineate the energetic mechanism underlying the decrease in functional """"""""reserve"""""""" and maximal work capacity of the hyperthyroid heart. The proposed studies are focused on three Specific Aims:
AIM I. Determine sequences contained in the 3'-untranslated region of alpha1-, alpha2-, and beta1-mRNA transcripts (cis-elements) and trans- acting factors that control the turnover of the mRNAs in the myocardium under basal and T3- stimulated conditions.
AIM II. Characterize cis-elements and trans-acting factors that control the translational efficiency of the different beta1- mRNA species expressed in the heart, and determine whether T3 has an effect on the control of translation.
AIM III. Determine the mechanism by which thyroid hormone controls the content of creatine-phosphocreatine pool in the heart, and define the role of altered creatine metabolism on the contractile function of the heart. Results of studies proposed in this project will increase our understanding of mechanisms mediating thyroidal regulation of myocardial Na, K-ATPase expression and cardiac bioenergetics. The studies are highly relevant to the pathogenesis of a variety of human diseases and conditions including congestive heart failure, salt and water imbalance, alterations in metabolism, and obesity.
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