The mammalian heart responds to a variety of humoral and hemodynamic stimuli with rapid and dramatic changes in the expression of specific genes. For example, the myosin heavy chain (MHC) composition of the rat heart is altered by thyroid hormone or pressure overload resulting in hearts with altered contractile velocity. Despite extensive documentation of changes in gene expression, very little is known about the molecular basis of cardiac gene regulation in vivo. While cis-acting regulatory sequences of several cardiac genes have been identified by transfection into cultured cells, these studies have been limited to phenomena which can be reproduced in vitro. This precludes the identification of regulatory elements which mediate the responses of various cardiac genes to complex stimuli such as hemodynamic pressure overload. Recently, we have utilized a method of introducing genes into the rat heart in vivo and established the feasibility of the approach for studying gene regulation. We propose to study cardiac myosin gen regulation in vivo and to identify those elements of MHC genes that mediate responses to stimuli at transcriptional land post transcriptional levels. First, we will determine the relative transcription rates of the alpha and beta cardiac MHC genes in hearts of rats in the following states: adult euthyroid, hypo-and hyperthyroid states, and pressure overload. Second, we will study two recently uncovered post- transcriptional events in alpha cardiac MHC gene expression. One appears to be an alternative splice near the 3"""""""" end of the gene which results in inclusion or exclusion of the glutamine residue. The second event is alternative sites of polyadenylation in which three different sites are utilized from a single canonical polyadenylation signal. We propose to investigate whether these two events are regulated and whether they require a cardiac cellular environment. Third, we will determine whether sequences in the alpha and beta MHC mRNAs contribute to MHC mRNA turnover in varying states where the MHC composition of the heart is known to change. Finally, using transgenic mice we will directly test whether changes in the myosin composition of the myocardium and in slow skeletal muscle affect function. This will be accomplished by making transgenic mice in which alpha MHC protein is expressed under the control of the beta MHC promoter and in which beta MHC protein is expressed under the control of the alpha MHC promoter.
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