Development of the heart requires the precise spatial and temporal control of gene expression for proliferation and differentiation. During embryonic and early neonatal development, the heart grows by cell proliferation. Further growth is later established through cell enlargement, or cardiac hypertrophy. Cardiac muscle cell proliferation appears to be regulated by a separate program, distinct from the program which controls differentiation of the myocyte, unlike most other cell types. The mechanisms governing the control of cardiomyocyte proliferation are yet to be established. An understanding of these mechanisms will provide an avenue of opportunity to manipulate cellular proliferation to replace and/or repair damaged tissue sustained from cardiovascular disease. We have identified, cloned and sequenced a novel gene (TAP) in the heart which is expressed in association with myocyte proliferation. Preliminary western analysis show that the Tap protein is expressed only in the dividing cardiomyocyte and is virtually absent from the non dividing myocyte. Our hypothesis predicts that TAP is a necessary component of a signal transduction pathway required for cardiomyocyte proliferation. Our long term goal is to determine the function of Tap in the dividing myocyte.
Our specific aims are to: (1) Identify cellular proteins which associated with Tap in the cardiomyocyte using the yeast two-hybrid screen and co-immunoprecipitation in order to determine how Tap may function in the cell. (2) To begin to functionally characterize Tap by over expressing and blocking its expression in cultured adult, 21-day postnatal and embryonic rat ventricular cardiomyocytes and in the HL-1 cardiac muscle cell line. Since this gene is entirely novel these studies will provide the first indication of the functional role of TAP in the myocyte, and provide a foundation for the design of rational, future in depth studies.
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