The long-term goal of our research program is to study the genetic regulation of proteins, which play a critical role in cardiac physiology. In particular, our studies focus on proteins of contractile apparatus and ion transport pumps. Since the primary step in the control of protein synthesis occurs at the level of transcription, the proposed studies will involve the detailed analysis of cis-DNA elements and transacting factors controlling gene expression. In this proposal, we will focus our attention on two cardiac muscle genes: 1) sarcoplasmic reticulum (SR) Ca2' ATPase, and 2) the ventricular myosin light chain (MLC1V). Specific-ally our goals are to focus our analysis on tissue specific regulation and to examine those involved in altering gene expression during adaptive growth resulting from pressure overload and thyroxine administration. To dissect the various regulatory elements, we will use in vitro cell culture models (cardiocytes and muscle cell lines); and in particular, we propose to use P19 embryonal carcinoma cells which have the potential to differentiate into cardiac cells. Once the cis-regulatory elements are identified, we will use them to characterize nuclear- regulatory proteins that interact with them. The final and long-term goal of this project is to develop methods to isolate CDNA clones/gene for the cardiac muscle specific regulatory proteins, and perform structure-function analysis of these molecules. Thus the overall emphasis of this proposal is to study and understand in detail how the control of transcription operates in cardiac muscle.
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